Show Summary Details
Page of

The Integrative Preventive Medicine Approach to Obesity and Diabetes 

The Integrative Preventive Medicine Approach to Obesity and Diabetes
Chapter:
The Integrative Preventive Medicine Approach to Obesity and Diabetes
Author(s):

David L. Katz

DOI:
10.1093/med/9780190241254.003.0018
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2020. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

date: 20 October 2020

Origins and Pathogenesis

The global prevalence of obesity has engendered understandable frustration among policy makers, public health practitioners, and healthcare providers alike. Attendant on this frustration has been a tendency to see obesity as complex. However, while resolving the modern obesity pandemic may indeed prove as complex as it is challenging, explaining it is easy. People who gain excess weight over time are in a state of positive energy balance. The longer that state persists, and the greater the imbalance, the more weight is gained.

There is a strong genetic contribution to obesity, mediated along several important pathways. Genes influence resting energy expenditure, thermogenesis, lean body mass, and appetite. There is, thus, an important potential genetic influence on both energy intake and expenditure. Overall, genetic factors are thought to explain roughly 40% of the variation in BMI. Adoption studies demonstrating an association between obesity in a child and the biological parents, despite rearing by surrogate parents, and twin studies showing anthropometric correspondence between identical twins reared apart are particularly useful sources of insight in this area1,2,3,4—genetic factors are of clinical importance as they help explain individual vulnerability to weight gain and its sequelae. Minimally, an appreciation for genetic factors in energy balance should foster insight and compassion relevant to clinical counseling. Maximally, elucidation of genetic contributions to obesity may illuminate novel therapeutic options over time.

Dozens of genes have been implicated as candidates for explaining, at least partly, susceptibility to obesity in different individuals; gene–gene interactions are highly probable in most cases.5,6,7,8,9 Only in rare instances is a monogenic explanation invoked. A variety of mutations may interfere with leptin signaling, and some of these may prove to be monogenic causes of obesity. In the most recent update from the Human Obesity Gene Map, 127 candidate genes for obesity-related traits were listed.10 Leptin, produced in adipose tissue, binds to receptors in the hypothalamus, providing information about the state of energy storage and affecting satiety.11,12 Binding of leptin inhibits secretion of neuropeptide Y, which is a potent stimulator of appetite.

The Ob gene was originally identified in mice, and Ob/Ob mice are deficient in leptin and obese.13 The administration of leptin to Ob/Ob mice results in weight loss. In humans, obesity is associated with elevated leptin levels.14 Nonetheless, the administration of leptin to obese humans has been associated with modest weight loss,15 suggesting that leptin resistance rather than deficiency may be an etiologic factor in some cases of human obesity.16 Leptin is the primary chemical messenger that signals adipocyte repletion to the hypothalamus; leptin resistance thus has the potential to delay or preclude satiety. The importance of leptin to the epidemiology of obesity has recently been reviewed.17,18,19,20 Much of the genetic influence on weight regulation may be mediated by variation in resting energy expenditure21 and appetite/satiety.

While the contribution of genes to obesity deserves both recognition and respect, it should not distract from the ultimate hegemony of environmental influences. Genes help explain varied susceptibility to, and expression of, obesity under any given set of environmental conditions. Stated another way, genes help explain the expanse of the “bell curve” characterizing the distribution of weight in a given population at a given time. Isolating the effects of genes on obesity from obesigenic elements in the environment is a considerable challenge;22 thinking of obesity as a product of gene–environment interaction in most cases may be the best means of meeting this challenge.23,24

Environmental factors better explain the position of that entire bell curve relative to a range of potential distributions. The genetic profile of US residents today, for example, may be quite similar to the profile 60 years ago, while the weight distributions for those two populations differ dramatically. The explanation for this divergence over time has much more to do with environmental change than with genetic change. This is true globally as well.

Initial research done in mouse models,25,26,27 followed by subsequent studies in humans,28,29,30 demonstrated distinct gut microbiota in obese as compared to lean individuals. Moreover, studies suggest that these differences in gut microbiota may influence energy balance and thus obesity.24 Interestingly, the effects of the microbiome on obesity seems to be transmissible. In mouse models, “transplantation” of gut microbes from obese mice to normal mice results in greater increases in total body fat as compared to those receiving microbes from lean mice.31 Although more research needs to be conducted before this becomes a mainstay of treatment, alterations of the gut microbiome through probiotics, antibiotics, and fecal transplantation open intriguing new pathways for the treatment of obesity.32,33

The balance referred to in “energy balance” is between energy units (typically, but not necessarily, measured in kilocalories or kilojoules) taken into the body and energy units expended by the body. Because the relationship between energy and matter is governed by fundamental laws of physics, the implications of energy balance are substantially self-evident. When more energy is taken into the body than is consumed by all energy-expending processes, the surplus is converted into matter. When energy expenditure exceeds energy intake, matter must be converted into energy to make up the deficit. Thus, positive energy balance increases a body’s matter, and negative energy balance decreases it. When energy intake and output are matched, matter—body mass in this case— remains stable.

Several details of clinical interest complicate this otherwise simple construct. The first is that while energy intake is limited to a single activity, eating, energy output is expressed in several ways, including thermogenesis, physical activity, basal metabolism, and growth. The second is that while excess energy intake is convertible into matter, the nature of that matter can vary. Namely, and in simple terms, excess calories can build lean body tissue, fat, or a combination of the two.

The calorie is a measure of food energy and represents the heat required to raise the temperature of 1 g, or cm3, of water by 1°C at sea level. A kilocalorie, the measure applied to foods, is the heat required to raise the temperature of 1 kg or L of water by the same extent, under the same conditions.34 The joule is an alternative measure of energy used preferentially in most applications other than food. The joule, and the corresponding kilojoule, is 4.184 times smaller than the calorie and kilocalorie, respectively.

There has been some recent controversy around the question “Is a calorie, a calorie?”35 A calorie is simply a unit of energy, and as such, 1 cal will always equal 1 cal (just as 1 mL will always equal 1 mL). Where the difference truly lies is that some foods are better for us than others, and one of the many virtues of better-for-us foods is that they tend to help us feel full on fewer calories and thus can tip the balance in the calories in, calories out equation.36 Calories consumed (“in”) is at least conceptually relatively simple: food. As noted, calories expended (“out”) is the more complicated combination of resting energy expenditure (REE), basal metabolic rate (BMR), physical activity, and thermogenesis. The formula includes energy dedicated to linear growth in children, which contributes to basal requirements. There is a limited literature to suggest an association between relatively greater protein intake and relatively higher REE at a given body mass than that associated with other macronutrient classes. Thermogenesis is influenced by sympathetic tone and leptin, which in turn may be influenced by insulin and, therefore, to some degree, by macronutrient distribution. A comparable number of calories from different macronutrient sources almost certainly will not be comparably satiating, so macronutrient distribution may influence satiety and, thereby, subsequent energy intake.

If an individual is genetically predisposed to insulin resistance, high levels of postprandial insulin may contribute to weight gain, all else being equal. If that individual restricts calories sufficiently, however, weight gain will not occur. But given the difficulty people with access to abundant and tasty food have restricting calories, the likelihood is that the individual will not do so effectively. High insulin levels may result in more efficient conversion of food energy to body fat, given adequate energy intake for fat deposition to occur. Body fat deposition will lead, in predisposed individuals, to the accumulation of visceral fat and thereby to more insulin resistance, raised insulin levels, and potentially more fat deposition. Thus, while the predominant dietary determinant of weight regulation is clearly total energy intake, macronutrient distribution, endocrine factors, and diverse genetic predispositions may contribute important mitigating influences at any given level of calorie consumption.

In essence, then, the pathogenesis of obesity involves the complex details of a very simple energy balance formula: When calories in exceed calories out, weight rises, and vice versa.

Theoretically, a pound of fat stores 4,086 kcal (9 kcal per g of fat, multiplied by the 454 g in a pound). However, a pound of living tissue is not actually just fat but must also contain the various structures and fluids required for the viability of that fat, such as blood, blood vessels, neurons, etc. By convention, an excess of 3,500 kcal is used to approximate the energy requirement for a pound of weight gain. By the same convention, a deficit of 3,500 kcal relative to expenditure will translate into a pound of body fat lost.

This thinking has evolved, however, informed by both theory and empirical evidence of neglected nuance. For one thing, as body mass increases, energy requirements for weight maintenance rise; and they fall as body mass declines. A more sophisticated view of the dynamic relationship between energy balance and weight change is fast supplanting the overly simplistic, static view that formerly prevailed.37,38

The complexity underlying the energy balance formula is reflected in a wide range of genetic, physiologic, psychological, and sociologic factors implicated in weight gain. Efforts to control weight, prevent gain, or facilitate loss must address energy balance to be successful. Control of body weight relies on achieving a stable balance between energy input and energy consumption at a desired level of energy storage.

Working against this goal is the natural tendency of the body to accumulate fat. The storage of energy in the form of adipose tissue is adaptive in all species with variable and unpredictable access to food. In humans, only about 1,200 kcal of energy is stored as glycogen in the prototypical 70 kg adult, enough to support a fast of 12 to 18 hours at most. A human’s ability to survive a more protracted fast depends on energy reserves in body fat, which average 120,000 kcal in a 70 kg adult. The natural tendency to store available energy as body fat persists, although the constant availability of nutrient energy has rendered this tendency maladaptive, whereas it once was, and occasionally still is, vital for survival.

The development of obesity appears to be related to an increase in both the size and number of adipocytes. Excess energy intake in early childhood and adolescence leads more readily to increases in fat cell number. In adults, excess energy consumption leads initially to increases in adipocyte size and only with more extreme imbalance to increased number. Childhood obesity does not lead invariably to adult obesity, as the total number of adipocytes in a lean adult generally exceeds the number in an obese child. Thus, correction for early energy imbalance can restore the number of adipocytes to the normal range. However, childhood obesity is a strong predictor of obesity, and its complications, in adulthood.39

In general, lesser degrees of obesity are more likely to be due to increased fat cell size, whereas more severe obesity often suggests increased fat cell number as well. Obesity due exclusively to increased adipocyte size is hypertrophic, whereas that due to increased fat cell number is hyperplastic. Weight loss apparently is more difficult to maintain in hyperplastic as compared to hypertrophic obesity because it requires reducing an abnormally high number of total adipocytes down to an abnormally low size. Adipocytes may actively regulate their size so that it is maintained within the normal range. Such signaling involves various chemical messengers released from adipose tissue, including angiotensinogen, tissue necrosis factor, and others, along with leptin. Adipocytes also produce lipoprotein lipase, which acts on circulating lipoprotein particles, especially very-low-density lipoprotein, to extract free fatty acids, which then are stored in the adipocyte as triglyceride.

The imbalance between energy consumption and expenditure that leads to excess weight gain can be mediated by either and generally is mediated by both. Relative inactivity and abundantly available calories both contribute.

On average, resting energy expenditure accounts for up to 70% of total energy expenditure, thermogenesis approximately 15%, and physical activity approximately 15%. The contribution of physical activity to energy expenditure is, of course, quite variable.

Resting energy expenditure can be measured by various methods, with the doubly labeled water method representing the prevailing standard in research settings.34,40 In clinical settings, basal energy requirements for weight maintenance can be estimated by use of the Harris-Benedict equation. A rough estimate of calories needed to maintain weight at an average level of activity is derived by multiplying the ideal weight of a woman (in pounds) by 12 to 14 and that of a man by 14 to 16. The REE is lower in women than in men when matched for height and weight due to the higher body fat content in women; muscle imposes a higher metabolic demand than fat at equal mass. A strong genetic component to the REE results in familial clustering as well as clustering within ethnic groups predisposed to obesity.41,42,43,44,45

The REE may fall by as much as 30% with dieting, although sustained reductions tend to be smaller, which explains why the maintenance of weight loss becomes increasingly difficult over time after initial success. The phenomenon of the “weight-loss plateau” is attributable in part to the equilibration of lower caloric intake with lower energy requirements resulting from reduced body mass. Weight-management counseling should anticipate and address this universal tendency.

Reductions in BMR may contribute as well to increasing difficulty in losing weight after successive attempts,46 although this concept is debated.47,48,49 A plausible mechanism is that both fat mass and lean body mass are reduced when calories are restricted, whereas weight regain due to caloric excess will result in an increase in fat mass preferentially. Thus, cycles of weight loss and regain have the potential to increase the percentage of body fat and thereby lower calorie requirements for maintenance at any given weight.

When exercise is used as a mainstay in weight loss or maintenance efforts, this mechanism is forestalled. Resistance training that builds muscle can increase BMR, both by increasing total body mass and/or by increasing the percentage of lean body mass. As muscle is more metabolically active than fat, the conversion of body mass from fat to muscle at a stable weight will increase BMR. This pattern may frustrate patients who rely on a scale to gauge weight loss success, but in fact a reduction in fat mass and an increase in lean body mass clearly is a weight management success and should be regarded as such, despite the unmoving dial on a bathroom scale. There is consensus among authorities that in those experiencing cardiometabolic complications of obesity, a weight reduction of 10% is often conducive to clinically important risk reduction. Less well described, but certainly plausible, is similar improvement in those who lower weight less but redistribute weight from fat to lean.

Energy expenditure per unit body mass peaks in early childhood due to the metabolic demands of growth. Total energy expenditure generally peaks in the second decade, and energy intake often does as well. Thereafter, energy requirements decline with age, as does energy consumption. Energy expenditure tends to decline more than energy intake, so that weight gain and, increasingly, adiposity are characteristic of aging.

It is of interest that the capacity of the body to store excess calories in an energy reserve composed of adipose tissue is adaptive in any environment imposing cyclical caloric deprivation. This tendency becomes maladaptive only when an excess of calories is continuously available. Also of note, the adaptive capacity for weight gain is generally variable among individuals and populations, and it is somewhat systematically variable between men and women.

Men are far more prone than premenopausal women to accumulate excess fat at the belly and within the abdominal viscera, rendering them more susceptible to cardiometabolic sequelae of obesity. The central pattern of obesity, known colorfully as the “apple” pattern, is referred to as android. In contrast, the “pear,” or peripheral, pattern of obesity is gynoid. There is a potential explanation for the tendency of women of reproductive age to store body fat more innocuously than men in evolutionary biology. Namely, reproduction depends on a woman’s ability to meet both her own caloric needs and those of a developing fetus. The capacity to create a large enough energy reserve to help ensure a successful pregnancy may be a critical, and of course uniquely female, adaptation. A final contribution to this admittedly speculative construct is made by the effects in women of reducing body fat content below a critical threshold. Menses ceases, and a state of infertility ensues. This effect is most commonly observed in young female athletes as well as girls with eating disorders, in whom it represents a threat of irreversible osteopenia.

Some ethnic groups are prone to the deposition of fat around the middle, and more importantly within the viscera, the liver in particular, with even minimal weight gain. This has led to the recognition of so-called lean obesity, in which the BMI is well below cutoffs for obesity or even overweight, but the metabolic complications of excess adiposity ensue nonetheless. These manifest generally as insulin resistance, with a high rate of progression to type 2 diabetes. Thus, the spectrum from obesity to diabetes, or “diabesity,” is not limited to obesity per se, but can be propagated by excess visceral adiposity in the absence of it.

Food ingestion increases sympathetic tone, raising levels of catecholamines as well as insulin. Brown adipose tissue, concentrated in the abdomen and present in varying amounts, functions principally in the regulation of energy storage and wastage by inducing heat generation in response to stimulation by catecholamines, insulin, and thyroid hormone. The increase in sympathetic tone postprandially results in thermogenesis (heat generation), which may consume up to 15% of ingested calories. Some researchers even suggest targeting thermogenesis for antiobesity efforts.50,51 A reduced thermic effect of food may contribute to the development of obesity, although this is controversial.52,53 Approximately 7% to 8% of total energy expenditure is accounted for by obligatory thermogenesis, but up to an additional 7% to 8% is facultative and may vary between the lean and obese.

Insulin resistance may be associated with reduced postprandial thermogenesis. However, obesity apparently precedes reduced thermogenesis, suggesting that impaired thermogenesis is unlikely as an explanation for susceptibility to obesity. Thermogenesis is related to the action of b3-adrenergic receptors, the density of which varies substantially. Reduced thermogenesis may contribute to weight gain with aging, as thermogenesis apparently declines with age, at least in men.54,55

Energy consumption generally has risen in industrialized countries over recent decades as both the energy density of the diet and portion sizes have increased. During the same period, energy expenditure generally has fallen, largely due to changes in the environment and the patterns of work and leisure activity. According to the most recent data from the CDC, a majority of Americans do not meet the physical activity recommendations of 30 minutes of moderate-intensity activities at least 5 days per week.56 A reduction in exercise-related energy expenditure contributes to energy imbalance and weight gain. The attribution of weight gain to physical inactivity is compounded by the associations between sedentary behavior and poor diet.57,58

Although there is consensus that physical activity is essential to long-term weight maintenance, the mechanisms of benefit remain controversial. Evidence that physical activity reduces food intake or results in extended periods of increased oxygen consumption is lacking, and there is evidence to the contrary. Exercise has the potential to increase the REE by increasing muscle mass. Energy consumption during exercise can help maintain energy balance.

Although the utility of physical activity per se in promoting weight loss is uncertain, lifetime physical activity apparently mitigates age-related weight gain and clearly is associated with important health benefits.59,60,61,62 Moreover, the argument that physical activity does not promote weight loss is flawed. Physical activity can indeed promote weight loss and burn fat but only if we engage in enough of it and do not then overeat. The problem is that even those of us who exercise daily are relatively sedentary by historical standards. In the obesigenic environment of the modern world, we are more prone to excessive energy intake and inadequate energy expenditure than any previous generation.63,64

The issue of whether physical activity and attendant fitness are more important to health than weight control has generated some controversy. Some authors have argued that fitness is more important than fatness, while others have defended the alternative view.65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86

This dispute may be more distracting than helpful. At the population level, most fit people are at least relatively lean, while relative fatness and lack of fitness similarly correlate. While “fit” might trump “fat” in terms of health effects, only an estimated 9% of the population resides in this category of both fit and fat.87 Evidence from large cohort studies suggests that fitness and fatness are independent predictors of health outcomes. The combination of fit and lean is clearly preferable over all others. Of the two, it appears that weight may influence outcomes slightly more strongly than fitness level.70

Evidence from the National Weight Control Registry suggests that regular physical activity may be an important element in lasting weight control.88,89 Physical activity is among the best predictors of long-term weight maintenance.90,91,92,93,94,95 It has been estimated that the expenditure of approximately 12 kcal per kg body weight per day in physical activity is the minimum protective against increasing body fat over time.93 The contribution of physical activity to weight maintenance may vary among individuals on the basis of genetic factors that are as yet poorly understood.96,97

Over recent years, there has been accumulating and encouraging evidence that lifestyle activity, as opposed to structured aerobic exercise, may be helpful in both achieving and maintaining weight loss.98 Such unobtrusive physical activity may be more readily accepted by exercise-averse patients.

Type 2 Diabetes Mellitus

The development of type 2 diabetes results from the interplay of genetic susceptibility and environmental factors.99 The responsible genes have not been identified with certainty, although multiple alleles are almost certainly involved, and certain candidate mutations have been under study for some time.100 The clustering of type 2 diabetes in families is well established. Interest in genetic susceptibility to type 2 diabetes dates at least to the early 1960s, when James Neel,101,102 who went on to head the human genome project, speculated that expression of diabetes was due to the confrontation of a thrifty metabolism designed for dietary subsistence with a world of nutritional abundance. The theory of metabolic thriftiness essentially posits that a brisk insulin release in response to ingestion is advantageous in the utilization and storage of food energy when such energy is only sporadically available. The same brisk response in the context of abundantly available nutrient energy leads to hyperinsulinemia, obesity, insulin resistance, and ultimately, with the advent of b-cell failure, diabetes. The thrifty genotype theory is supported by certain lines of evidence but is far from universally accepted and continues to generate considerable interest and debate.103,104,105,106,107,108

Factors associated with expression of the disease include excessive nutrient energy intake with resultant obesity, physical inactivity, and advancing age. These factors contribute to the development of insulin resistance at the receptor, an often key element in the development of type 2 diabetes mellitus. Physical activity appears to protect against the advent of type 2 diabetes mellitus both independently and by preventing and mitigating weight gain and obesity.109 As with type 1 diabetes, the role of the microbiome is currently of intense interest.

Insulin resistance generally precedes, by an uncertain and probably variable period of time, the development of diabetes, although type 2 diabetes can develop in the absence of insulin resistance.110,111,112 Diabetes generally occurs when receptor-mediated resistance is compounded by b-cell dysfunction and reduced insulin secretion. Basal insulin production in a healthy, lean adult is roughly 20 to 30 units per 24-hour period. In insulin resistance, that output may be as much as quadrupled to maintain euglycemia. Type 2 diabetes following insulin resistance indicates the failure of b-cells to sustain supraphysiologic output of insulin, a decline of insulin output to below normal levels, and the consequent advent of hyperglycemia.113,114 Whereas type 1 diabetes is associated with nearly absent insulin release (0 to 4 units daily), type 2 diabetes is generally thought to emerge in lean individuals when production falls to approximately 14 units per day.

An association between weight gain and the development of diabetes is supported by prospective cohort studies,115,116,117 although insulin resistance may contribute to the development of obesity as well, so that causality may be bidirectional.118 Data from such sources suggest that weight loss is protective against the development of diabetes. The currently worsening epidemic of obesity in the United States suggests that the prevalence of diabetes will likely rise and that efforts to combat obesity, if ultimately successful, will translate into reduced rates of diabetes as well.

The incidence of type 2 diabetes in the pediatric population parallels the increase in pediatric obesity.119 A generation ago, type 2 diabetes was called “adult-onset” diabetes to distinguish it from “juvenile-onset” diabetes. What was a chronic disease of midlife has become an increasingly routine pediatric diagnosis.120,121,122

The Adult Treatment Panel of the National Cholesterol Education Program has essentially equated diabetes with established coronary disease in its guidance for cardiac risk factor management.123 With adult-onset diabetes now seen in children younger than age 10, we may anticipate the emergence of cardiovascular disease (CVD) in ever younger individuals.124,125

The development and manifestations of insulin resistance relate to the principal actions of insulin. In the liver, insulin inhibits gluconeogenesis, inhibits glycogenolysis, and promotes glycogen production.126 In muscle and adipose tissue, insulin facilitates the uptake of glucose as well as its use and storage. Insulin exerts important influences on protein and lipid metabolism as well. The fundamental role of insulin is to coordinate the use and storage of food energy. This requires regulation of both carbohydrate and fat metabolism, as total body glycogen and glucose stores in a healthy adult approximate 300 g. At 4 kcal per g, this represents an energy reserve of 1,200 kcal, enough to support a fast of approximately 12 to 18 hours. Energy stored as triglyceride in adipose tissue in a lean adult totals nearly 120,000 kcal, or 100 times the carbohydrate reserve. Thus, release of energy stores from adipose tissue can protect vital organs during a protracted fast.

In the fed state, the entry of amino acids and monosaccharides into the portal circulation stimulates release of proinsulin from pancreatic b-cells. Insulin is cleaved from the connecting (“C”) protein to generate active insulin. Insulin transports both amino acids and glucose into the liver, where it stimulates glycogen synthesis, protein synthesis, and fatty acid synthesis, while suppressing glycogenolysis and gluconeogenesis as well as proteolysis and lipolysis. Insulin carries both glucose and amino acids into skeletal muscle, and it carries glucose into adipose tissue. Insulin facilitates glycogen synthesis and glycolysis in muscle, and it facilitates fatty acid synthesis in adipose tissue. Insulin also stimulates the synthesis of lipoprotein lipase in capillaries, facilitating the extraction of fatty acids from circulation, and promotes hepatic very-low-density lipoprotein (VLDL) synthesis.

During a fast, insulin levels decline, as levels of glucagon, a product of the pancreatic a-cells, rise. Falling insulin levels promote glycogenolysis, followed by gluconeogenesis, in the liver. In adipose tissue, low insulin levels stimulate lipolysis, releasing fatty acids for use as fuel; ketones are generated in the process of hepatic fatty acid oxidation. High levels of circulating fatty acids inhibit insulin action. Reduced insulin action at skeletal muscle stimulates proteolysis.

In the insulin-resistant state, insulin levels are high, but receptors, particularly those on skeletal muscle, are relatively insensitive to insulin action.127,128 High levels of insulin presumably compensate for receptor-mediated resistance. High insulin levels promote fatty acid synthesis in the liver. The accumulation and circulation of free fatty acids and triglycerides packaged in VLDL aggravate insulin resistance, driving insulin levels higher. Thus, the metabolic derangements are self-perpetuating, generating in the process the manifestations of the insulin-resistance syndrome associated with cardiovascular risk, until the b-cells fail and diabetes develops.

With b-cell failure, the resultant low levels of circulating insulin mimic conditions during a fast. The metabolic derangements that distinguish diabetes from fasting include pathologically low insulin levels and, of course, high levels of circulating glucose. Hepatic gluconeogenesis compounds the hyperglycemia, with excess glucose leading to tissue damage through glycosylation. Glycosylation of hemoglobin is routinely used as a measure of the extent of prevailing glycemia (i.e., HgbA1c). High ambient levels of glucose lead to the production of sugar alcohols (e.g., sorbitol, fructose) in many tissues, which in turn can cause cellular distention. The accumulation of such polyols in the lens is causally implicated in the blurred vision that often occurs with poorly controlled diabetes.

In studies of the Pima Indians, a tribe of Native Americans particularly subject to the development of obesity and diabetes mellitus, Lillioja et al129 showed that insulin resistance is an antecedent of diabetes. During the phase of insulin resistance, serum glucose is normal but insulin levels are abnormally elevated, both in the fasting and postprandial states. The development of obesity appears to be of particular importance in the development of IGT secondary to insulin resistance. A modest degree of hyperglycemia may occur during the period of insulin resistance, acting as a signal to the endocrine pancreas that insulin action is impaired and stimulating more insulin release. Ultimately, both protracted hypersecretion and hyperglycemia may contribute to b-cell dysfunction and overt diabetes.

The development of type 2 diabetes often is preceded by a protracted period of insulin resistance manifested as the “metabolic syndrome” of obesity, dyslipidemia, and hypertension. Abdominal obesity and hypertriglyceridemia may be particularly early markers of the syndrome and represent a readily detectable indicator of risk for diabetes.130 Of note, the defining features of the insulin-resistance syndrome, and the nomenclature applied, have been matters of contention. The American Heart Association supports diagnostic criteria for the metabolic syndrome,131 while the American Diabetes Association has questioned the utility of defining a syndrome at all.132

Regardless of the terminology applied to the various manifestations of the insulin-resistant state, interventions to treat the condition, particularly supervised weight loss, may both mitigate associated cardiovascular risk and prevent the evolution of diabetes. The Diabetes Prevention Program has provided definitive evidence that intervention with either lifestyle modification or pharmacotherapy can prevent type 2 diabetes in a significant proportion of at-risk individuals.133 In individuals with diagnosed type 2 diabetes, the Look AHEAD trial has demonstrated that intensive lifestyle intervention can improve glucose control and reduce CVD risk factors and medication use.134,135

Epidemiology

In the United States, obesity is among the gravest and most poorly controlled public health threats of our time.136,137,138 Over two-thirds of the adults in the United States are overweight or obese. Recent data suggest that the prevalence of obesity may have plateaued for some age groups over the past few years.139,140 While this may offer a glimmer of hope, there are less sanguine interpretations of the data. A plateau in any trend is inevitable as the limits of its range are approximated. Further, the prevalence of overweight and obesity does not adequately reflect the distribution of actual weights in the population.

There is evidence that the more extreme degrees of obesity are increasing in prevalence faster than overweight.141 This suggests that the minority in the population that has resisted the tendency toward excessive weight gain thus far may remain resistant and not contribute to the ranks of the overweight and obese. Those, however, who have already succumbed to obesity trends may remain vulnerable to increasing weight gain over time, thus transitioning through overweight to progressively severe degrees of obesity. This implies that even if the cumulative prevalence of overweight and obesity were to stabilize at current levels, the health effects of obesity may well continue to worsen. Compounding such concerns, the most recent trend data indicate continued, significant increases in obesity prevalence for women and for children and adolescents in the United States; insignificant increases for men; and increases in severe obesity for all groups.142,143

The rate of childhood obesity has tripled in the past two decades.144 Over 30% of children in the US population at large are considered overweight or obese. In some ethnic minority groups, this figure rises to 40%.140

Recent studies indicate that obesity is occurring at ever-younger ages. A marked rise in the prevalence of overweight among infants and toddlers has been documented both in the United States and globally.145,146 As in adults, BMI is a crude indicator of adiposity and fat distribution in children. Data indicate that waist circumference has been rising in tandem with BMI in children, which is of concern since abdominal adiposity has worse health implications.147

The increasingly global economy has rendered obesity an increasingly global problem, with the United States the putative epicenter of an obesity pandemic.148,149,150 Worldwide, an estimated 1.4 billion adults are overweight or obese.151 Rates of obesity are already high and rising in most developed countries, and they are lower but rising faster in countries undergoing a cultural transition.152 In China, India, and Russia, the constellation of enormous population, inadequate control of historical public health threats such as infectious disease, and the advent of epidemic obesity and attendant chronic disease represent an unprecedented challenge.153,154,155 In countries undergoing a time of even more rapid cultural transition and development, the effects on obesity and chronic disease are astonishing. For example, in Qatar, the rates of obesity and diabetes are even higher than those in the United States, with 75% of adults overweight or obese and 17% of adults with type 2 diabetes.156

Obesity control is among the current priorities the World Health Organization. Universal dietary preferences evidently predominate over cultural patterns as nutrient-dilute, energy-dense foods become available.157,158 At the 10th International Congress on Obesity held in Sydney, Australia, in September 2006, World Health Organization data were reported, indicating that for the first time in history, there were more overweight than hungry people on the planet.

The fundamental health implications of obesity appear to be universal. Appropriate threshold values for the definition of overweight and obesity, however, should likely vary with ethnicity and associated anthropometry. Certain Asian populations appear to have a predilection for central, and visceral, fat deposition and thus a vulnerability to insulin resistance at a BMI deemed normal and innocuous for most occidental populations. There are noteworthy variations in BMI, waist circumference, and lean body mass among diverse ethnic groups. Genetic variability in the susceptibility to obesity and its metabolic sequelae is quite pronounced.

In the United States, there are some 25.8 million diabetics, of whom roughly 18.8 million are diagnosed and the remainder undiagnosed.159,160 The ratio of diagnosed to undiagnosed diabetes has declined slightly over recent years among the overweight, apparently in response to heightened awareness of diabetes risk in this group.160 More than 90% of the diagnosed cases and virtually all of the undiagnosed cases of diabetes are type 2. Prediabetes, encompassing both IGT (a blood sugar level of 140 to 199 mg per dL after a 2-hour oral glucose tolerance test) and IFG (blood sugar level of 100 to 125 mg per dL after an overnight fast), affects some 79 million.159 The metabolic or insulin-resistance syndrome now affects nearly one-fourth of US adults, and some 80 million or more are insulin resistant.161,162

The World Health Organization estimates that there were approximately 347 million diabetics worldwide as of 2012, and it projects that diabetes deaths will increase by two-thirds between 2008 and 2030.163 Projections in the United States suggest that nearly 1 in 3 individuals born in the year 2000 or after will develop diabetes in their lifetime, and for Hispanics, the figure is nearly 1 in 2.164,165,166 Some more recent projections are more dire still, pointing to diabetes in 40% of the general population and 50% or more in certain ethnic groups.167 Other data indicating modest improvement in recent trends support somewhat less ominous projections.168

Sequelae

The health consequences of obesity are in general well characterized, as is the economic toll.169,170,171,172,173,174,175,176,177 The toll of the epidemic is most starkly conveyed by the impact on children. The claim has been made that due to epidemic obesity, we are now raising the first generation of children with a shorter projected life expectancy than that of their parents.169,178 This view has been contested, however, with claims that life expectancy will continue to rise into the future despite a rising burden of chronic disease.

Obesity, at least when distributed centrally, engenders a plethora of cardiac risk factors and is thus an important contributor to cardiovascular disease. An observational cohort study conducted by the American Cancer Society179 representing more than 15 million person years of observation has demonstrated a link between obesity and most cancers. Obesity is associated with asthma, sleep apnea, osteoarthritis, and gastrointestinal disorders as well.

Obesity in children has been linked to increased risk of developing hypertension,180,181,182,183 hypercholesterolemia,184,185 hyperinsulinemia,184 insulin resistance,186,187 hyperandrogenemia,186,187 gallstones,65,188,189 hepatitis and fatty liver,190,191,192,193 sleep apnea,194,195,196,197,198 orthopedic abnormalities (e.g., slipped capital epiphyses),199,200,201,202,203 and increased intracranial hypertension.204,205,206,207,208,209 Obesity during adolescence increases rates of cardiovascular disease210,211,212,213,214 and diabetes211,215 in adulthood, in both men and women. In women, adolescent obesity is associated with completion of fewer years of education, higher rates of poverty, and lower rates of marriage and household income. In men, obesity in adolescence is associated with increased all-cause mortality and mortality from cardiovascular disease and colon cancer.211,216 Adults who were obese as children have increased mortality and morbidity, independent of adult weight.39,211,217-219 Childhood obesity appears to be accelerating the onset of puberty in girls and may delay puberty in boys.220

Reports that weight cycling may be associated with morbidity or mortality, independently of obesity, are of uncertain significance.219,221-223 There is evidence that when other risk factors are adequately controlled in the analysis, weight cycling does not predict mortality independently of obesity.224,225,226 There is also evidence that cardiovascular risk factors are dependent on the degree of obesity and fat accumulation over time rather than weight regain following loss.227,228 The benefits of weight loss are thought to override any potential hazards of weight regain;229 therefore, efforts at weight loss generally should be encouraged even in obese individuals with a prior history of weight cycling.230 However, repeated cycles of weight loss and regain may render subsequent weight loss more difficult by affecting body composition and metabolic rate, although this is an area of some controversy. For this reason, among others, weight-loss efforts should be predicated on sustainable adjustments to diet and lifestyle, whenever possible, rather than extreme modifications over the short term.

Often overlooked but of clear relevance to office-based dietary counseling is the relationship between obesity and mental health. Body image, adversely affected and even distorted by obesity, is important to self-esteem.231,232 Thus, poor self-esteem is a common consequence of obesity (the converse often also being true, with poor self-esteem adversely affecting diet).233 This has important implications for dietary modification efforts. Repeated cycles of weight loss and regain may have particularly adverse effects on psychological well-being, although research in this area is limited.221,234,235

Evidence consistently and clearly indicates that obesity engenders antipathy, resulting in stigma, social bias, and discrimination.231,236,237 Obese children suffer from poor self-esteem233,238,239 and are subjected to teasing, discrimination, and victimization.217,240,241 Bullying and weight status can develop into a vicious cycle in which the stress of being teased may make the child more likely to seek out comfort food, thus further hindering the chance of achieving a healthy weight. The topic of weight bias is of ever-increasing concern as the worsening epidemic of obesity directs increasing societal attention to the topic.

The severity of prejudice against obesity is startling. Studies among schoolchildren consistently indicate a strong and nearly universal distaste for obesity as compared to other and equally noticeable variations in physiognomy.

In addition to its obvious implications for the overall well-being of obese persons, weight bias has implications for public policy. There is some evidence to suggest that the routine measurement of student BMI by schools, with reports home to parents, may enhance awareness of, and responses to, childhood obesity. This intervention was implemented successfully in Arkansas and is thought to have contributed to an apparent turnaround in childhood obesity trends in the state.242 Nonetheless, there is considerable opposition to this strategy, due largely to its potential for stigmatizing obese children and vilifying their parents.243 The solution to weight bias, however, cannot be to deny the problem of obesity. Rather, obesity and prejudice must both be confronted. And when the problem of obesity is attacked, it must be consistently and abundantly clear that the attack is against the condition and its causes, not its victims. All clinicians share in the responsibility for highlighting this distinction. As is true of the metabolic effects of obesity, psychosocial sequelae of the condition tend to vary with its severity.244

Type 2 diabetes is often, although not always, a complication of obesity. It, in turn, may be complicated by all of the end-organ injuries associated with type 1 diabetes, from the heart and vasculature, to the eyes, nerves, limbs, and kidneys.

Obesity and Mortality

One of the most contentious and controversial aspects of the obesity epidemic has been a reliable accounting of the mortality toll. In 1993, McGinnis and Foege245 identified the combination of dietary pattern and sedentary lifestyle as the second leading cause of preventable, premature death in the United States, accounting for some 350,000 deaths per year. Obesity contributes to the majority of these deaths and was considered to be directly or indirectly responsible for approximately 300,000 annual deaths.246

Calle et al247 reported a linear relationship between BMI and mortality risk, based on an observational cohort of more than 1 million subjects followed for 14 years. In this cohort, high BMI was less predictive of mortality risk in blacks than in whites. Manson et al248 found a linear relationship between BMI and mortality risk in women from the Nurses’ Health Study; the lowest risk of all-cause mortality occurred in women with a BMI 15% below average with stable weight over time.

In a study of over half a million adults by Adams et al,249 after controlling for smoking status and initial health, both overweight and obesity was associated with an increased risk of death. More recently, a highly publicized meta-analysis by Flegal et al250 found that while obesity was associated with a higher all-cause mortality relative to normal weight, overweight was associated with a significantly lower all-cause mortality rate.

There is now a rich litany of arguments on both sides of the obesity/mortality divide, with arguments for and against a high mortality toll now178,251-253 and in the future. The CDC has officially addressed the controversy on more than one occasion, with much of the debate spilling over into the popular press.246,254-282

Masters et al, adjusting for birth cohort, demonstrated a high and rising contribution of obesity to mortality moving through the past toward the present.283 Other important considerations are that some obesity is metabolically innocuous, while metabolically significant “obesity” can occur in the context of a normal BMI; both of these bias the BMI/mortality association toward the null. In addition, studies showing null or inverse associations between BMI and mortality have often failed to exclude those with cachexia related to ill health at baseline.

Fortunately, there is no need to reach absolute consensus on the death toll of obesity to appreciate the threat it represents. It may be that obesity is killing fewer people than projected because of advances in tertiary care. Certainly the means of compensating for chronic diseases in advanced states improve with each passing year. But compensation for chronic disease by such means as endovascular procedures, polypharmacy, and/or surgery is not nearly as good as, and is vastly more expensive than, preserving good health. That obesity accounts for an enormous burden of chronic disease is beyond dispute; it lies on the well-established causal pathway toward virtually all of the leading causes of premature death and disability in industrialized countries, including diabetes, cardiovascular disease, cancer, degenerative arthritis, dementia, stroke, and, to a lesser extent, obstructive pulmonary disease. Thus, while the number of years obesity may be taking out of life is debatable, there is no argument that it is taking life out of years.

There is, finally, a simple logic about the association between obesity and mortality. Obesity contributes mightily to the prevalence of diabetes, cancer, heart disease, and, to a lesser extent, stroke. These, in turn, are the leading proximal causes of death in the United States. It would seem far-fetched that a condition contributing to all the leading causes of death is entirely unimplicated itself.

Economic Toll of Obesity

Overweight and obesity are thought to add an estimated $113 billion to national health-related expenditures in the United States each year or fully 5% to 10% of the nation’s medical bill.284 Obesity has been a major driver of increased Medicare expenditures over the past decade.285 Compared to medical spending on healthy weight adults, medical spending on obese adults may be as much as 100% higher.171 Additionally, if the current childhood obesity epidemic is not halted, researchers forecast that from 2030 to 2050, there will be an additional $254 billion of obesity-related costs from both direct medical costs and loss of productivity.286

There is also evidence to suggest that obesity results in personal financial disadvantage; poverty is predictive of obesity, and obesity is also predictive of less upward financial mobility.287,288,289 Thorpe et al285 have attributed to obesity alone 12% of the increase in healthcare spending in the United States over recent years.290,291 Obesity-related expenditures by private insurers purportedly increased 10-fold between 1987 and 2002.

A report in the American Journal of Health Promotion292 indicates that obesity increases healthcare- and absenteeism-related costs by $460 to $2,500 per worker per year. Roughly one-third of this cost is induced by higher rates of absenteeism, and two-thirds are induced by healthcare expenditures. These costs are distributed to lean workers as well, who pay higher healthcare premiums as a result, and to the employer, who experiences higher operating costs.

But some may actually profit from obesity, notably those in businesses responsible for selling the excess calories that make weight gain possible. In a provocative piece in the Washington Post, Michael Rosenwald293 suggested that obesity is an integral aspect of the American economy, influencing industries as diverse as food, fitness, and healthcare. The trade-off between obesity-related profits and losses has been considered elsewhere.294 Costs and benefits are often a matter of perspective, and what is good finance for the seller may be bad for the buyer.

Close and Schoeller295 have pointed out that bargain pricing on oversized fast-food meals and related products actually increases net cost to the consumer, largely as a consequence of weight gain. The higher costs over time relate to adverse health effects of obesity as well as increased food intake by larger persons. Note the paradox here: In order to sustain the market for the excess calories that contribute to obesity, obesity is necessary, as it drives up the calories required just to maintain weight; obesity depends on an excess of calories, and the effective peddling of that excess of calories depends on obesity.

Another cost of obesity is reduced fuel efficiency when driving and carrying more weight. Stated bluntly, the “all-you-can- eat” buffet is not much of a bargain both because excess calories resulting in excess weight lead to increased costs of living and because most beneficiaries of discounted dietary indulgences wind up willing to spend a fortune to lose weight they gained at no extra charge. There may be some utility in pointing this out to patients.

The Integrative Preventive Medicine Approaches to Clinical Treatment

Bariatric surgery of varying types is well established as efficacious treatment for severe or complicated obesity. Pharmacotherapy for obesity per se is rather less convincingly supported in the literature, but the mere existence of FDA-approved drugs for weight loss and management bespeaks a relevant body of evidence. Pharmacotherapy for type 2 diabetes is, of course, the standard of practice, and an area of bountiful and ever-evolving evidence.

Relative inattention to these topics here is not indicative of their unimportance; rather the contrary. These approaches are promoted by the prevailing forces and profit centers of modern medicine, and thus predominate. Consequently, the attendant literature is vast, continuously refreshed, and readily accessible to all, including excellent, current reviews on each of these topics. For that reason, then, this chapter will focus preferentially on those aspects of treatment rooted in lifestyle, and generally relegated to lesser, supporting roles.

Evidence that sustainable weight loss is enhanced by means other than caloric restriction is lacking. Whereas short-term weight loss is consistently achieved by any dietary approach to the restriction of choice and thereby calories, lasting weight control is not. Competing dietary claims imply that fundamental knowledge of dietary pattern and human health is lacking; an extensive literature belies this notion. The same dietary and lifestyle pattern conducive to health promotion is consistently associated with weight control. A bird’s-eye view of the literature on diet and weight reveals a forest otherwise difficult to discern through the trees. Competing diet claims are diverting attention and resources from what is actually and urgently needed: a dedicated and concerted effort to make the basic dietary pattern known to support both health and weight control more accessible to all.

Against the backdrop of this increasingly acute need, the identification of practical and generalizable solutions to the obesity crisis has proved elusive. From research interventions, to commercial weight loss programs, to supplements, potions, and devices, innumerable approaches to weight loss have been devised. That none of these has yet met the need of the population is clearly reflected in the stubborn epidemiology of obesity.

Obesity is as relevant to prevailing views on beauty, fashion, and body image as it is to public health, and thus it engenders unique preoccupations.296,297,298,299,300,301,302 Individuals reluctant to take antihypertensive or lipid-lowering medication for fear of side effects may aggressively pursue pharmacotherapy, or even surgery, for weight control.303,304,305 The visibility of obesity, the stigma associated with it306,307,308 (it is often said that antiobesity sentiment is the last bastion of socially acceptable prejudice), and the difficulty most people experience in their efforts to resist it contribute to its novel influences on attitude and behavior. This widespread state of volatile frustration renders the public susceptible to almost any persuasive sales pitch for a weight-loss lotion, potion, or program.

The natural consequence of acute and substantially unmet need is frustration. This public frustration has created a seemingly limitless market for weight-loss approaches. This same frustration has engendered a prevailing gullibility so that virtually any weight-loss claim is accepted at face value. Dual aphorisms might be considered for characterizing the obesity epidemic. Until recently, organized responses to this degenerating crisis have been tepid at best, suggesting that among public health professionals, familiarity breeds complacency, if not outright contempt. Among members of the general public, desperation breeds gullibility.

It is thus a seller’s market for weight-loss wares. The litany of competing claims for effective weight loss is producing increasing confusion among both the public at large and healthcare professionals.309 In the mix is everything from science to snake oil, with no assurances that science is the more popular choice.

The concept of the “ideal” body weight and efforts to reach it may be both unrealistic and harmful for most overweight patients. The benefits of moderate weight loss are sufficiently clear to justify efforts to induce a loss of 5% to 10% of total weight, which is apt to be much more readily achievable. Perhaps better still is an emphasis on the means of achieving weight loss—namely changes in diet and activity pattern rather than weight per se, as the patient has control over the former but can only indirectly influence the latter. Most adult patients concerned about weight regulation will have made multiple attempts at weight control, with at best transient success. Above all, clinicians must not submit to “blame the victim” temptations in this setting.

Temporary weight loss is no more a definitive resolution of the metabolic factors that promote obesity than transient euglycemia is a resolution of diabetes. Therefore, diets designed for short-term weight loss offer no convincing benefit either in terms of sustained weight loss or health outcomes. Because dietary and lifestyle management of weight must be permanent, it is essential that the dietary patterns applied be compatible with recommendations for health promotion in general. Fad diets promoted for purposes of rapid weight loss are unsubstantiated in the peer-reviewed literature. Even if conducive to weight management over time, such diets would be ill advised unless shown to promote health and prevent disease.

Several general modifications of the overall dietary pattern are likely to facilitate weight control. Some benefit may derive from frequent, small meals or snacks rather than the conventional three meals a day. One study examining snacking habits in overweight women enrolled in a weight- loss study found that mid-morning snackers lost more weight than afternoon or evening snackers.310 Physiologically, there is some evidence that distributing the same number of calories in small snacks (“nibbling”) rather than larger meals (“gorging”) may reduce 24-hour insulin production, at least in insulin-resistant individuals.311 Speechly et al312 reported evidence that snacking attenuates appetite relative to larger meals spaced farther apart. A group of seven obese men was provided an ad libitum lunch following a morning “preload” provided as a single meal or multiple snacks with the same total nutrient and energy composition. Subjects ate significantly (27%) less following multiple small meals than after a single larger one. Insulin peaked at higher levels following the single meal and was sustained above baseline for longer with the multiple small meals. Total area under the insulin curves was similar in both groups.

Evidence in support of “snacking” as a means of controlling weight or improving insulin metabolism is preliminary and not undisputed.313,314 However, there is generally a profound psychological component to disturbances of weight regulation, and the distribution of meals and calories may be germane. Most patients trying to control their weight are both tempted by and afraid of preferred foods. Consequently, many such patients resist eating for protracted periods during the day, only to overindulge in a late-day or evening binge. This pattern perpetuates a dysfunctional and tense relationship between the patient and his or her diet.

Patients caught up in this pattern may benefit from advice to bring nutrient dense, wholesome, satiating foods with them every day and systematically to resist foods made available by others. Patients should be encouraged to eat whenever they want, but only those foods chosen in advance. By having free access to such foods (e.g., fresh fruits, fresh vegetables, nuts, etc.), patients may overcome their fear of needing to “go hungry” for extended periods each day. In addition, frequent snacking during the day obviates the need and desire for a compulsive and binge-like meal at the end of the day. Finally, for many patients, the ideal time for exercise is after work. Overweight patients who have avoided food much of the day may simply be too hungry after work to exercise. A meal at such a time often is prepared impulsively and eaten not only to satisfy energy needs but also to assuage the pent-up frustrations of the day. On questioning, many overweight patients acknowledge that they often eat, and overeat, for reasons having nothing to do with hunger.

Exercise is an effective means of moderating psychological stress315 and may attenuate the need to resolve such stress with food. In addition, exercise may temporarily suppress appetite and generally enhance self-esteem, both of which are conducive to more thoughtful choices as the evening meal is prepared. Finally, and most evident, is the additional caloric expenditure resulting from the added activity. A meta-analysis of weight-loss studies published in 1997 reveals important limitations in the field of obesity management but suggests that best results to date have been achieved by combining energy-restricted diets with aerobic exercise.316

The primary clinical intervention for weight management is lifestyle counseling. The case for universal weight-management counseling in clinical care has not yet been made on the basis of evidence. The US Preventive Services Task Force recommends intensive dietary counseling for patients with overt cardiovascular risk factors and routine screening for obesity, but it concludes that evidence is insufficient to support routine dietary or weight-management counseling for adults without known hypertension, hyperlipidemia, cardiovascular disease, or diabetes.317,318,319

For the most part, effective and practical methods of obesity prevention in clinical context are as yet not reliably established.

Relatively few interventions have been conducted that aim to introduce such counseling into the native environments of clinical practice, and even fewer have demonstrated efficacy of low-intensity interventions, such as brief counseling sessions with the primary care clinician.320 There are exceptions, however,321 with more attention thus far to physical activity than to diet.322,323,324,325,326

There is suggestive evidence that physician counseling of overweight patients is supportive of weight loss and of the use of appropriate methods to achieve such weight loss.327 Overall, evidence in support of counseling is limited, largely because such counseling is limited;328 the only effective interventions appear to be those of medium- and high-intensity behavioral counseling.318

Worth noting in societies such as the United States, which has both highly prevalent obesity and preoccupation with slimness, is a tendency for even normal-weight individuals to “diet.” In addition, such injudicious practices as smoking may be used as a means to maintain body weight.329 The clinician should be equally prepared to discourage ill-advised weight control practices as to encourage salutary ones. There is some evidence that patients who discuss weight control with their healthcare providers are more apt to pursue weight loss and control by healthful and prudent means.327,330 Also noteworthy is increasing recognition of the need to reform clinical practice patterns on the basis of both available evidence and professional judgment.

Encouraging patients to eat well for the promotion of health and the prevention and/or amelioration of disease should be approached in the context of well-established principles of behavior modification. Some patients need to be motivated before they are willing to consider change, others need help strategizing to maintain change currently under way, and still others need help overcoming the sequelae of prior failed attempts. This latter group, perhaps predominant, may be harmed by counseling efforts focusing only on motivation. Much effort at dietary modification fails due to the diverse and challenging obstacles to a healthy diet in the modern “toxic” nutritional environment. The clinician committed to promoting the nutritional health of patients must commit to devising strategies, tailored to individual patients, over and around such obstacles.

Relevant models of behavior modification encompass motivational interviewing; the transtheoretical model; adaptations of these specific to the primary care setting; and the social ecological model.

Several salient principles warrant particular emphasis here. First, given the prevalence of obesity, counseling for weight control should be universal. Second, given the popularity of weight-loss approaches that diverge from well-established practice for health promotion, the principal focus of weight control efforts should, in fact, be health. The best available evidence links dietary and activity patterns conducive to health with long-term maintenance of weight. Third, given that obesity is epidemic in both adults and children, the unit to which counseling should be aimed is the family or household rather than the individual patient. Adult patients have a responsibility to engage their children in healthful lifestyle practices, and they will find lifestyle change easier and more sustainable for themselves when the effort involves household-wide solidarity. Finally, weight control efforts should be directed toward long-term sustainability rather than the fast start that seems perennially tantalizing to patients.

A final, important consideration is that clinical approaches to the obesity/diabetes spectrum invite, if they do not require, attention to holism. All too often a platitude, holistic care can and should be approached as a practicable, replicable, and testable method. As such, its relevance to weight management is particularly salient.

Consider a woman of roughly 70, who comes to the clinic ostensibly to get dietary advice because she wants to lose weight. She is, indeed, obese—with a body mass index of 32. She has high blood pressure and type 2 diabetes, and is on medication for these. Her husband passed away 4 years ago, and she lives alone. She is lonely, tends toward sadness, and is always tired. She sleeps poorly.

She eats in part because she is often hungry, in part to get gratification she does not get from other sources. She does not exercise because she has arthritis that makes even walking painful. Her arthritis has worsened as her weight has gone up, putting more strain on already taxed hips and knees. Medication for her joint pains irritates her stomach, and worsens her hypertension. And so on.

Such a patient, likely familiar to all clinician readers, is, in the coarse vernacular of medicine, circling the drain. A complex array of medical, emotional, and social problems really can resemble a cascade in which each malady worsens another, and the net effect is a downward spiral into despondent disability. “Circling the drain” is crude, but apt.

The term actually has hidden utility. If one can descend one degenerating spiral at a time, there is reason to think treatment can reverse engineer the process, allowing for ascent in much the same fashion. This is what holistic care—in its practical details—needs to be; both when practiced by a healthcare professional and in the context of self-care by patients. There are no magical means by which a complex array of interconnected problems can be fixed in one fell swoop. But this array can be appreciated, deconstructed, and addressed in a logical sequence that is respectful of the whole, even while managing it in parts.

For the hypothetical case in question, and innumerable real people like her, reversing a descent begins with one well-prioritized move in the other direction. So, for instance, it is likely that this woman has markedly impaired sleep, due perhaps to sleep apnea. A test and intervention to address this effectively may be the best first move for a number of reasons.

Poor sleep can cause, and/or compound depression; poor sleep invariably lowers pain thresholds, making things hurt that otherwise might not, and things that would hurt anyway, hurt more; poor sleep leads to unrestrained and emotional eating; poor sleep leads to hormonal imbalances that foster hypertension, insulin resistance, and weight gain; and poor sleep saps energy that might otherwise be used for everything from social interactions, to exercise.

Whether a focus on sleep is the right first step will vary with the patient, of course. If it is, as soon as sleep does improve, the benefits start to accrue. Our patient has a bit less pain, a bit more energy, and a slightly more hopeful outlook. So now that she has some more resources, we ask more of her. We are devoted to her, and on her team, but that only means we will hold her hand—not carry her. So, we now need her to invest these benefits back into herself.

The energy available now but not before allows for the start of a gentle exercise regimen (water-based if need be to avoid joint strain). Mobility in turn allows for social activity of interest to get some stimulation and purpose reintroduced into her life. Now, or soon, the process of dietary improvements to address the weight loss goals initially espoused can begin.

We might also start a course of massage therapy or acupuncture to further alleviate joint pain, now that our patient believes feeling better is possible, and is thus motivated to try new things.

A little exercise further improves energy, and sleep, and self-esteem, and actually helps ease joint pain. Less pain further improves energy, sleep, and the willingness, maybe even eagerness, to exercise. Social engagement—perhaps in a church or civic group—confers gratification that no longer needs to come from food. Hormonal rebalancing that occurs with restoration of circadian rhythms alleviates constant hunger. Diet improves. Medication doses are dialed down. Helpful supplements may be started.

Weight loss starts. Energy goes up. Joint pain improves some more. Physical activity becomes less and less problematic, and increases incrementally. Energy and sleep improve further, weight loss picks up. With more hope, and more opportunity to get out, our patient establishes, or reestablishes, social contacts that restore friendship and love to their rightful place in her life. Her spirit rises, and with it, the energy she has to invest back into her own vitality.

And so on, with many details left out, of course, and unique to any given patient. This may sound like wishful thinking—but it is a rewarding reality seen routinely in the context of holistic clinical approaches to the seemingly isolated challenge of weight management, and its associated morbidities.

A Role for Technology in the Integrated Preventive Medicine Remedy

By supplanting physical activity, technology, notably “screen time,” has long been implicated among the causes of obesity. There is now rapid development in the use of technology-based solutions, spanning both innovative hardware and software, the latter most commonly in the form of applications, or “apps,” for smartphones. This area is evolving so rapidly that any summary verdict is sure to be obsolete by the time it is read. Readers are encouraged to monitor developments in this area. For now, what may be said is that there is a literature to support at least the promise of technology-based contributions to the prevention and management of both obesity and diabetes.331,332

Culture, in Integrated Preventive Medicine Context

Clinicians will, in fact, not be the solution to the problem of epidemic obesity, as many components of a comprehensive weight-management campaign that would satisfy population needs fall outside the clinical purview. But clinicians have a vital role to play, as both educators and advocates. And given the magnitude and urgency of this crisis, to do otherwise is simply no longer acceptable. We have a choice of being part of the solution or, failing that, being part of a status quo that propagates the problem. As the IOM outlines in its recent report on obesity prevention, we need healthcare providers to adopt standards of practice for prevention, screening, diagnosis, and treatment of overweight and obesity; emphasize pre-pregnancy counseling on maintenance of a healthy weight before, during, and after pregnancy; and advocate publically for healthy communities that support healthy eating and active living.333

In the weight-loss literature, interventions achieve caloric restriction by various means, ranging from direct provision of food,334 systems of incentive/disincentive,335 cognitive-behavioral therapy,336 fat restriction,337 and the color-coding of food choices based on nutrient density.338 In general, those interventions achieving the most extreme degrees of caloric restriction also produce the greatest initial weight loss. However, a rebound weight gain is typically observed; in general, the more rapid the initial weight loss, the greater and more rapid the subsequent weight gain.339,340 This observation appears to be of generalizable significance, likely due to the fact that the extreme caloric restriction necessary for very rapid weight loss is intrinsically unsustainable. When the means used to achieve initial weight loss are unsustainable, weight regain is consistently observed.

Where the spectrum from obesity to type 2 diabetes is most reliably prevented, and where that is done in the context of the true “prize” at which all healthcare is ostensibly directed, the combination of vitality and longevity, the principal means to such ends are not clinical. Nor are they a matter of the triumph of personal will and responsibility over adverse elements in the social and cultural environment. Rather, they are a product of culture itself.

This is epitomized by the world’s so-called Blue Zones, representing the populations identified to date with the highest concentrations of healthy centenarians.

Related work attributes such advantages to lifestyle, but not to medicine. Clinical counseling does not figure among the explanations for Blue Zone blessings; rather, the explanations all reside at the level of culture.341

If anything, our culture is prone to “overmedicalization,”342 for reasons we might readily suppose. Even the currently massive societal preoccupation with so-called healthcare reform343 is principally about access to care for the treatment of illness, and much less about building health at its origins in daily living.

We have long had indications of this societal bias. Nearly two decades of effort were required before clear evidence supporting a lifestyle intervention as an alternative to coronary bypass surgery resulted in comparable reimbursement.344 Our society readily accepts the bill for bariatric surgery in obese adolescents, while neglecting potentially better, less medical remedies.345 To the extent that we medicalize obesity, we may divert both attention and resources away from cultural and environmental responses to it.346

The importance of the built environment347 and public polices348 in the epidemiology of obesity and chronic disease are well established. There is evidence as well of the favorable impact of community-wide interventions that treat a population, rather than an individual, as the patient.349 And, of course, there is the flagrant if uncontrolled evidence of our recent cultural history. Obesity and its metabolic sequelae were relatively rare before the advent of highly obesigenic environmental and cultural conditions, and became prevalent in tandem with their proliferation. During this time, genes and metabolic pathways changed not at all, while prevailing dietary and activity patterns changed substantially. Purists might fuss over the want of randomized clinical trials to establish true causality here, but there are no clinical trials to substantiate the link between striking a match and starting a fire either.

The role of clinicians in lifestyle medicine varies with circumstance. In the case of advanced metabolic complications, it is inevitably a large role. In the case of lifestyle and weight management counseling, it is a supporting role, but an important one nonetheless. We can and should cultivate widespread competency in constructive, compassionate, and streamlined counseling.350 We can, and should, design programs for finding health and losing weight that involve clinicians strategically, while sparing them excessive burdens of time and effort.351

There is a strong case for better application of lifestyle in medicine, and the engagement of clinicians in the delivery of effective programming and constructive counseling. There is, perhaps, particular promise here in efforts to control, curtail, and reverse both obesity and type 2 diabetes. But populations around the world enjoying the longest, happiest, most vital lives do not attribute such blessings preferentially to clinical care, but rather to culture. Lifestyle in medicine, laudable though it may be, and preferable as it is to the omission of lifestyle from medical practice, raises the prospect of overmedicalization if we stop there. If we stop there, we fail to concede that lifestyle actually happens not in hospitals and clinics, but in the places people live and learn, work and play, eat and pray, and love. We are thus duty bound to exert a collective, salutary influence beyond the halls of medicine where disease care is concentrated, propagating the practice of “health” care throughout culture itself.

Source

Katz DL, with Friedman RSC, Lucan S.Nutrition in Clinical Practice. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins/Wolters Kluwer; 2014.Find this resource:

References

1. Rasmussen F, Kark M, Tholin S, et al. The Swedish Young Male Twins Study: a resource for longitudinal research on risk factors for obesity and cardiovascular diseases. Twin Res Hum Genet 2006;9(6):883–839.Find this resource:

2. Hakala P, Rissanen A, Koskenvuo M, et al. Environmental factors in the development of obesity in identical twins. Int J Obes Relat Metab Disord 1999;23(7):746–753.Find this resource:

3. Koeppen-Schomerus G, Wardle J, Plomin R. A genetic analysis of weight and overweight in 4-year-old twin pairs. Int J Obes Relat Metab Disord 2001;25(6):838–844.Find this resource:

4. Echwald S. Genetics of human obesity: lessons from mouse models and candidate genes. J Intern Med 1999;245:653–666.Find this resource:

5. Perusse L, Bouchard C. Genotype-environment interaction in human obesity. Nutr Rev 1999;57(5 pt 2):s31–s37.Find this resource:

6. Bell CG, Walley AJ, Froguel P. The genetics of human obesity. Nat Rev Genet 2005;6(3):221–234.Find this resource:

7. Walley AJ, Asher JE, Froguel P. The genetics contribution to non-syndromic human obesity. Nat Rev Genet 2009;10(7):431–442.Find this resource:

8. Cheung WW, Mao P. Recent Advances in obesity: genetics and beyond. ISRN Endocrinol 2012;2012:1–11.Find this resource:

9. Rankinen T, Zuberi A, Chagnon YC, et al. The human obesity gene map: the 2005 update. Obesity 2006;14(4):529–644.Find this resource:

10. Clement K. Leptin and the genetics of obesity. Leptin and the genetics of obesity. Acta Paedietr Suppl 1999;88:51–57.Find this resource:

11. Marti A, Berraondo B, Martinez J. Leptin: physiological actions. J Physiol Biochem 1999;55:43–49.Find this resource:

12. Lonnquist F, Nordfors L, Schalling M. Leptin and its potential role in human obesity. J Intern Med 1999;245:643–652.Find this resource:

13. Ronnemaa T, Karonen S-L, Rissanen A, et al. Relation between plasma leptin levels and measures of body fat in identical twins discordant for obesity. Ann Intern Med 1997;126:26–31.Find this resource:

14. Heymsfield S, Greenberg A, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999;282:1568–1575.Find this resource:

15. Hamann A, Matthaei S. Regulation of energy balance by leptin. Exp Clin Endocrinol Diabetes 1996;104:293–300.Find this resource:

16. Enriori PJ, Evans AE, Sinnayah P, et al. Leptin resistance and obesity. Obesity (Silver Spring) 2006;14(Suppl 5):254S–258S.Find this resource:

17. Zhang Y, Scarpace PJ. The role of leptin in leptin resistance and obesity. Physiol Behav 2006;88(3):249–256.Find this resource:

18. Paracchini V, Pedotti P, Taioli E. Genetics of leptin and obesity: a HuGE review. Am J Epidemiol 2005;162(2):101–114.Find this resource:

19. Oswal A, Yeo G. Leptin and the control of body weight: a review of its diverse central targets, signaling mechanisms, and role in the pathogenesis of obesity. Obesity 2010;18(2):221–229.Find this resource:

20. Ravussin E. Energy metabolism in obesity: studies in the Pima Indians. Diabetes Care 1993;16(1):232–238.Find this resource:

21. Konturek SJ, Konturek JW, Pawlik T, et al. Brain-gut axis and its role in the control of food intake. J Physiol Pharmacol 2004;55(1 Pt 2):137–154.Find this resource:

22. Bouchard C. Gene-environment interactions in the etiology of obesity: defining the fundamentals. Obesity 2008;16(S3):S5–S10.Find this resource:

23. Qi L, Cho YA. Gene-environment interaction and obesity. Nutr Rev 2008;66(12):684–694.Find this resource:

24. Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity- associated gut microbiome with increased capacity for energy harvest. Nature 2006; 7122(444):1027–1031.Find this resource:

25. Turnbaugh PJ, Bäckhed F, Fulton L, et al. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 2008;3(4):213–223.Find this resource:

26. Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A 2004;101(44):15718–15723.Find this resource:

27. Turnbaugh PJ, Gordon JI. The core gut microbiome, energy balance and obesity. J Physiol (Lond) 2009;587(pt 17):4153–4158.Find this resource:

28. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature 2009;457(7228):480–484.Find this resource:

29. Ley RE. Obesity and the human microbiome. Curr Opin Gastroenterol 2010;26(1):5–11.Find this resource:

30. Schwiertz A, Taras D, Schafer K, et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 2010;18:190–195.Find this resource:

31. Kootte RS, Vrieze A, Holleman F, et al. The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus. Diabetes Obes Metab 2012;14(2):112–120.Find this resource:

32. Vrieze A, Holleman F, Serlie MJ et al. Metabolic effects of transplanting gut microbiota from lean donors to subjects with metabolic syndrome. Diabetologia 2010;53:S44–S44.Find this resource:

33. Holt SH, Miller JC, Petocz P, et al. A satiety index of common foods. Eur J Clin Nutr 1995;49(9):675–690.Find this resource:

34. Schoeller, D., Recent advances from application of doubly labeled water to measurement of human energy expenditure. J Nutr 1999;129:1765–1768.Find this resource:

35.Is-a-Calorie-a-Calorie? 2012. http://opinionator.blogs.nytimes.com.

36.Calories. http://www.huffingtonpost.com/david-katz-md/calories_b_1369749.html.

37. Chow CC, Hall KD. Short and long-term energy intake patterns and their implications for human body weight regulation. Physiol Behav 2014;134:60–65.Find this resource:

38. Hall KD. Modeling metabolic adaptations and energy regulation in humans. Annu Rev Nutr 2012;32:35–54.Find this resource:

39. Reilly JJ, Kelly J. Long-term impact of overweight and obesity in childhood and adolescence on morbitdity and premature mortality in adulthood: systematic review. Int J Obes 2005 2011;35(7):891–898.Find this resource:

40. Schoeller DA. Insights into energy balance from doubly labeled water. Int J Obes (Lond) 2008;32(suppl 7):S72–S75.Find this resource:

41. Rush E, Plank L, Robinson S. Resting metabolic rate in young Polynesian and Caucasian women. Int J Obes Relat Metab Disord 1997;21:1071–1075.Find this resource:

42. Ravussin E, Gautier J. Metabolic predictors of weight gain. Int J Obes Relat Metab Disord 1999;23(Suppl 1):37–41.Find this resource:

43. Luke A, Dugas L, Kramer H. Ethnicity, energy expenditure and obesity: are the observed black/white diferences meaningful? Curr Opin Endocrinol Diabetes Obes 2007;14(5):370–373.Find this resource:

44. Gannon B, DiPietro L, Poehlman ET. Do African Americans have lower energy expenditure than Caucasians? Int J Obes Relat Metab Disord 2000;24(1):4–13.Find this resource:

45. Sun M, Gower BA, Bartolucci AA, et al. A longitudinal study of resting energy expenditure relative to body composition during puberty in African American and white children. Am J Clin Nutr 2001;73(2):308–315.Find this resource:

46. Astrup A, Gotzsche P, Werken KD, et al. Meta-analysis of resting metabolic rate in formerly obese subjects. Am J Clin Nutr 1999;69:1117–1122.Find this resource:

47. Weinsier RL, Nagy TR, Hunter GR, et al. Do adaptive changes in metabolic rate favor weight gain in weight- reducing individuals? An examination of the set point theory. Am J Nutr 2007;72(5):1088–1094.Find this resource:

48. Byrne NM, Wood RE, Schutz Y, et al. Does metabolic compensation explain the majority off less-than-expected weight loss in obese adults during a short-term severe diet and exercise intervention? Int J Obes (Lond) 2012;36(11):1472–1478.Find this resource:

49. Maclean PS, Bergouignan A, Cornier M-A, et al. Biology’s response to dieting: the impetus for weight regain. Am J Physiol Regul Integr Comp Physiol 2011;301(3):R581–R600.Find this resource:

50. Wijers SL, Saris WH, Van Marken Lichtenbelt WD. Recent advances in adaptive thermogenesis: potential implications for the treatment of obesity. Obes Rev 2009;10(2):218–226.Find this resource:

51. Clapham JC, Arch JRS. Targeting thermogenesis and related pathways in anti-obesity drug discovery. Pharmacol Ther 2011;131(3):295–308.Find this resource:

52. Stock M. Gluttony and thermogenesis revisited. Int J Obes Relat Metab Disord 1999;23:1105–1117.Find this resource:

53. Lowell BB, Bachman ES.β‎-Adrenergic receptors, diet-induced thermogenesis, and obesity. J Biol Chem 2003;278(32):29385–29388.Find this resource:

54. Kerckhoffs D, Blaak E, Baak MV, et al. Effect of aging on beta-adrenergically mediated thermogenesis in men. Am J Physiol 1998;274:E1075–E1079.Find this resource:

55. Saely CH, Geiger K, Drexel H. Brown versus white adipose tissue: a mini-review. Gerontology 2012;58(1):15–23.Find this resource:

56. Centers for Disease Control and Prevention. US Physical Activity Statistics. 2010.Find this resource:

57. Gillman MW, Pinto BM, Tennstedt S, et al. Relationships of physical activity with dietary behaviors among adults. Prev Med 2001;32(3):295–301.Find this resource:

58. Simoes E, Byers T, Coates R, et al. The association between leisure-time physical activity and dietary fat in American adults. Am J Public Health 1995;85:240–244.Find this resource:

59. Dipietro L. Physical activity in the prevention of obesity: current evidence and research issues. Med Sci Sports Exerc 1999;31(11 suppl):s542–s546.Find this resource:

60. Goldberg JH, King AC. Physical activity and weight management across the lifespan. Annu Rev Public Health 2007;28:145–170.Find this resource:

61. Jakicic JM, Davis KK. Obesity and physical activity. Psychiatr Clin North Am 2011;34(4): 829–840.Find this resource:

62. Catenacci VA, Wyatt HR. The role of physical activity in producing and maintaining weight loss. Nat Clin Pract Endocrinol Metab 2007;3(7):518–529.Find this resource:

63.Exercise-of-Math-and-Myth. 2012. http://health.usnews.com/health-news/blogs/eat-run/.

64. Katz DL. Unfattening our children: forks over feet. Int J Obes (Lond) 2011;35(1):33–37.Find this resource:

65. Holcomb GW Jr, O’Neill JA Jr, Holcomb GW. Cholecystitis, cholelithiasis and common duct stenosis in children and adolescents. Ann Surg 1980;191(5):626–635.Find this resource:

66. Christou DD, Gentile CL, DeSouza CA, et al. Fatness is a better predictor of cardiovascular disease risk factor profile than aerobic fitness in healthy men. Circulation 2005;111(15):1904–1914.Find this resource:

67. Eisenmann JC, Wickel EE, Welk GJ, et al. Relationship between adolescent fitness and fatness and cardiovascular disease risk factors in adulthood: the Aerobics Center Longitudinal Study (ACLS). Am Heart J 2005;149(1):46–53.Find this resource:

68. Norman AC, Drinkard B, McDuffie JR, et al. Influence of excess adiposity on exercise fitness and performance in overweight children and adolescents. Pediatrics 2005;115(6):e690–e696.Find this resource:

69. Coakley EH, Kawachi I, Manson JE, et al. Lower levels of physical functioning are associated with higher body weight among middle-aged and older women. Int J Obes Relat Metab Disord 1998;22(10):958–965.Find this resource:

70. Hu FB, Willett WC, Li T, et al. Adiposity as compared with physical activity in predicting mortality among women. N Engl J Med 2004;351(26):2694–2703.Find this resource:

71. Weinstein AR, Sesso HD, Lee IM, et al. Relationship of physical activity vs body mass index with type 2 diabetes in women. JAMA 2004;292(10):1188–1194.Find this resource:

72. Fang J, Wylie-Rosett J, Cohen HW, et al. Exercise, body mass index, caloric intake, and cardiovascular mortality. Am J Prev Med 2003;25(4):283–289.Find this resource:

73. Haapanen-Niemi N, Miilunpalo S, Pasanen M, et al. Body mass index, physical inactivity and low level of physical fitness as determinants of all-cause and cardiovascular disease mortality—16 y follow-up of middle-aged and elderly men and women. Int J Obes Relat Metab Disord 2000;24(11):1465–1474.Find this resource:

74. Martinez ME, Giovannucci E, Spiegelman D, et al. Leisure-time physical activity, body size, and colon cancer in women. Nurses’ Health Study Research Group. J Natl Cancer Inst 1997;89(13):948–955.Find this resource:

75. Giovannucci E, Ascherio A, Rimm E, et al. Physical activity, obesity, and risk for colon Cancer and Adenoma in Men. Ann Intern Med 1995;122:327–334.Find this resource:

76. Patel AV, Rodriguez C, Bernstein L, et al. Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. Cohort. Cancer Epidemiol Biomarkers Prev 2005;14(2):459–466.Find this resource:

77. Wei M, Kampert JB, Barlow CE, et al. Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight, and obese men. JAMA 1999;282(16):1547–1553.Find this resource:

78. Katzmarzyk PT, Janssen I, Ardern CI. Physical inactivity, excess adiposity and premature mortality. Obes Rev 2003;4(4):257–290.Find this resource:

79. Wessel TR, Arant CB, Olson MB, et al. Relationship of physical fitness vs body mass index with coronary artery disease and cardiovascular events in women. JAMA 2004;292(10):1179–1187.Find this resource:

80. Lee DC, Sui X, Blair SN. Does physical activity ameliorate the health hazards of obesity? Br J Sports Med 2009;43(1):49–51.Find this resource:

81. Fogelholm M. Physical activity, fitness and fatness: relations to mortality, morbidity and disease risk factors: a systematic review. Obes Rev 2010;11(3):202–221.Find this resource:

82. Kwon S, Burns TL, Janz K. Associations of cardiorespiratory fitness and fatness with cardiovascular risk factors among adolescents: the NHANES 1999–2002. J Phys Act Health 2010;7(6):746–753.Find this resource:

83. Woo J, Yu R, Yau F. Fitness, fatness and survival in elderly populations. Age (Dordrecht, Netherlands) 2013;35(3):973–984.Find this resource:

84. Hainer V, Toplak H, Stich V. Fat or fit: what is more important? Diabetes Care 2009;32(Suppl 2):S392–S397.Find this resource:

85. Suriano K, Curran J, Byrne SM, et al. Fatness, fitness, and increased cardiovascular risk in young children. J Pediatr 2010;157(4):552–558.Find this resource:

86. McAuley P, Pittsley J, Myers J, et al. Fitness and fatness as mortality predictors in healthy older men: the veterans exercise testing study. J Gerontol A Biol Sci Med Sci 2009;64A(6):695–699.Find this resource:

87. Duncan GE. The “fit but fat” concept revisited: population-based estimates using NHANES. Int J Behav Nutr Phys Act 2010;7:47.Find this resource:

88. Phelan S, Wyatt HR, Hill JO, et al. Are the eating and exercise habits of successful weight losers changing? Obesity (Silver Spring) 2006;14(4):710–716.Find this resource:

89. Wing RR, Hill JO. Successful weight loss maintenance. Annu Rev Nutr 2001;21:323–341.Find this resource:

90. Zachwieja JJ. Exercise as a treatment for obesity. Endocrinol Metab Clin North Am 1996;25(4):965–988.Find this resource:

91. Doucet E, Imbeault P, Almeras N, et al. Physical activity and low-fat diet: is it enough to maintain weight stability in the reduced-obese individual following weight loss by drug therapy and energy restriction? Obes Res 1999;7:323–333.Find this resource:

92. Rippe JM, Hess S. The role of physical activity in the prevention and management of obesity. J Am Diet Assoc 1998;98(10 Suppl 2):S31–S38.Find this resource:

93. Saris W. Exercise with or without dietary restriction and obesity treatment. Int J Obes Relat Metab Disord 1995;1995(Suppl 4): S113–S116.Find this resource:

94. Mekary RA, Feskanich D, Hu FB, et al. Physical activity in relation to long-term weight maintenance after intentional weight loss in premenopausal women. Obesity 2010;18(1):167–174.Find this resource:

95. Lee I, Djousse L, Sesso HD, et al. Physical activity and weight gain prevention. JAMA 2010;303(12):1173–1179.Find this resource:

96. Heitmann B, Kaprio J, Harris J, et al. Are genetic determinants of weight gain modified by leisure-time physical activity? A prospective study of Finnish twins. Am J Clin Nutr 1997;66:672–678.Find this resource:

97. Andersen R, Wadden T, Bartlett S, et al. Effects of lifestyle activity vs structured aerobic exercise in obese women: a randomized trial. JAMA 1999;281(4):335–340.Find this resource:

98. Eaton S, Eaton SB 3rd, Konner M. Paleolithic nutrition revisited: a twelve-year retrospective on its nature and implications. Eur J Clinical Nutrition 1997;51:207–216.Find this resource:

99. Lebovitz H. Type 2 diabetes: an overview. Clin Chem 1999;45:1339–1345.Find this resource:

100. Drong AW, Lindgren CM, McCarthy MI. The genetic and epigenetic basis of type 2 diabetes and obesity. Clin Pharmacol Ther 2012;92(6):707–715.Find this resource:

101. Resnicow K.Cancer Prevention and Comprehensive School Health Education: The Role of the American Cancer Society. Paper presented at the American Cancer Society National Conference, Atlanta, GA. May 28–30, 1991.Find this resource:

102. Neel, J. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Human Genetics 1962;14:353–362.Find this resource:

103. Benyshek DC, Watson JT. Exploring the thrifty genotype’s food-shortage assumptions: a cross-cultural comparison of ethnographic accounts of food security among foraging and agricultural societies. Am J Phys Anthropol 2006;131:120–126.Find this resource:

104. Prentice AM. Early influences on human energy regulation: thrifty genotypes and thrifty phenotypes. Physiol Behav 2005;86:640–645.Find this resource:

105. Prentice AM, Rayco-Solon P, Moore SE. Insights from the developing world: thrifty genotypes and thrifty pheno-types. Proc Nutr Soc 2005;64:153–161.Find this resource:

106. Chakravarthy MV, Booth FW. Eating, exercise, and “thrifty” genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases. J Appl Physiol 2004;96(1):3–10.Find this resource:

107. Speakman JR. Thrifty genes for obesity and the metabolic syndrome—time to call off the search? Diab Vasc Dis Res 2006;3:7–11.Find this resource:

108. Dulloo AG, Jacquet J, Seydoux J, et al. The thrifty “catch-up fat” phenotype: its impact on insulin sensitivity during growth trajectories to obesity and metabolic syndrome. Int J Obes (Lond) 2006;30:S23–S35.Find this resource:

109. Allen DB, Nemeth BA, Clark RR, et al. Fitness is a stronger predictor of fasting insulin levels than fatness in overweight male middle-school children. J Pediatr 2007;150:383–387.Find this resource:

110. Goldfine AB, Bouche C, Parker RA, et al. Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease. Proc Natl Acad Sci USA 2003;100:2724–2729.Find this resource:

111. Kadowaki T. Insights into insulin resistance and type 2 diabetes from knockout mouse models. J Clin Invest 2000;106:459–465.Find this resource:

112. Cavaghan MK, Ehrmann DA, Polonsky KS. Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. J Clin Invest 2000;106:329–333.Find this resource:

113. Leahy JL. Pathogenesis of type 2 diabetes mellitus. Arch Med Res 2005 May–June; 36(3):197–209.Find this resource:

114. Meece J. Pancreatic islet dysfunction in type 2 diabetes: a rational target for incretin-based therapies. Curr Med Res Opin 2007;23:933–944.Find this resource:

115. Colditz GA, Willett WC, Rotnitzky A, et al. Weight gain as a risk factor for clinical diabetes mellitus in women [see comments]. Ann Intern Med 1995;122(7):481–486.Find this resource:

116. Ford E, Williamson D, Liu S. Weight change and diabetes incidence: findings from a national cohort of US adults. Am J Epidemiol 1997;146:214.Find this resource:

117. Biggs ML, Mukamal KJ, Luchsinger JA, et al. Association between adiposity in midlife and older age and risk of diabetes in older adults. JAMA 2010;303(24):2504–2512.Find this resource:

118. Lazarus R, Sparrow D, Weiss S. Temporal relations between obesity and insulin: longitudinal data from the normative aging study. Am J Epidemiol 1998;147:173–179.Find this resource:

119. Aye T, Levitsky LL. Type 2 diabetes: an epidemic disease in childhood. Curr Opin Pediatr 2003;15:411–415.Find this resource:

120. Fagot-Campagna A, Pettitt DJ, et al. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr 2000;136(5):664–672.Find this resource:

121. Pontiroli AE. Type 2 diabetes mellitus is becoming the most common type of diabetes in school children. Acta Diabetol 2004;41(3):85–90.Find this resource:

122. Wiegand S, Maikowski U, Blankenstein O, et al. Type 2 diabetes and impaired glucose tolerance in European children and adolescents with obesity—a problem that is no longer restricted to minority groups. Eur J Endocrinol 2004;151(2):199–206.Find this resource:

123. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486–2497.Find this resource:

124. Apedo MT, Sowers JR, Banerji MA. Cardiovascular disease in adolescents with type 2 diabetes mellitus. J Pediatr Endocrinol Metab 2002;15(Suppl 1):519–523.Find this resource:

125. Steinberger J, Daniels SR. Obesity, insulin resistance, diabetes, and cardiovascular risk in children: an American Heart Association scientific statement from the Artherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Nutrition, Physical Activity, and Metabolism). Circulation 2003;107:1448–1453.Find this resource:

126. Moller D, Flier J. Insulin resistance-mechanisms, syndromes, and implications. N Engl J Med 1991;325:938–948.Find this resource:

127. Ye J. Role of insulin in the pathogenesis of free fatty acid-induced insulin resistance in skeletal muscle. Endocr Metab Immune Disord Drug Targets 2007;7: 65–74.Find this resource:

128. Sesti G. Pathophysiology of insulin resistance. Best Pract Res Clin Endocrinol Metab 2006;20:665–679.Find this resource:

129. Lillioja S, Mott D, Spraul M, et al. Impaired glucose tolerance as a disorder of insulin action. N Engl J Med 1988;318:1217–1225.Find this resource:

130. Grundy S. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol 1999;83(9B):25F–29F.Find this resource:

131. American Heart Association. Metabolic Syndrome. http://www.americanheart.org/presenter.jhtml?identifier=4756; accessed3/20/13.

132. Kahn R, Buse J, Ferrannini E, et al; for the American Diabetes Association and the European Association for the Study of Diabetes. The metabolic syndrome: time for a critical appraisal (ADA statement). Diabetes Care 2005;28:2289–2304.Find this resource:

133. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346(6): 393–403.Find this resource:

134. Look AHEAD Research Group, Pi-Sunyer X, Blackburn G, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care 2007;30(6):1374–1383.Find this resource:

135. Look AHEAD Research Group, Wing RR. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med 2010;170(17):1566–1575.Find this resource:

136. Mascie-Taylor CG, Karim E. The burden of chronic disease. Science 2003;302:1921–1922.Find this resource:

137. Tillotson JE. Pandemic obesity: what is the solution? Nutr Today 2004;39(1):6–9.Find this resource:

138. Jeffery RW, Utter J. The changing environment and population obesity in the United States. Obes Res 2003;11:12S–22S.Find this resource:

139. Flegal KM, Carroll MD, Kit BK, et al. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA 2012;307(5):491–497.Find this resource:

140. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999–2010. JAMA 2012;307(5):483–490.Find this resource:

141. Sturm R, Hattori A. Morbid obesity rates continue to rise rapidly in the United States. Int J Obes 2013;37(6):889–891.Find this resource:

142. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA 2016;315(21):2284–2291.Find this resource:

143. Ogden CL, Carroll MD, Lawman HG, et al. Trends in Obesity Prevalence Among Children and Adolescents in the United States, 1988–1994 through 2013–2014. JAMA 2016;315(21):2292–2299.Find this resource:

144. Ogden CL, Carroll MD, Flegal KM. Epidemiologic trends in overweight and obesity. Endocrinol Metab Clin North Am 2003;32:741–760.Find this resource:

145. Kim J, Peterson KE, Scanlon KS, et al. Trends in overweight from 1980 through 2001 among preschool-aged children enrolled in a health maintenance organization. Obesity (Silver Spring) 2006;14(7):1107–1112.Find this resource:

146. de Onis M, Blössner M, Borghi E. Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr 2010;92(5):1257–1264.Find this resource:

147. Li C, Ford ES, Mokdad AH, et al. Recent trends in waist circumference and waist-height ratio among US children and adolescents. Pediatrics 2006;118(5):e1390–e1398.Find this resource:

148. Chopra M, Galbraith S, Darnton-Hill I. A global response to a global problem: the epidemic of overnutrition. Bull World Health Organ 2002;80:952–958.Find this resource:

149. Damcott CM, Sack P, Shuldiner AR. The genetics of obesity. Endocrinol Metab Clin North Am 2003;32:761–786.Find this resource:

150. Katz DL. Pandemic obesity and the contagion of nutritional nonsense. Public Health Rev 2003;31:33–44.Find this resource:

151. World Health Organization. Cardiovascular Diseases—Fact sheet N°317. 2011. http://www.who.int/mediacentre/factsheets/fs317/en/index.html.

152. Drewnowski A. Nutrition transition and global dietary trends. Nutrition 2000;16:486–487.Find this resource:

153. Silventoinen K, Sans S, Tolonen H, et al. WHO MONICA Project. Trends in obesity and energy supply in the WHO MONICA Project. Int J Obes Relat Metab Disord 2004;28:710–718.Find this resource:

154. Misra A, Vikram NK. Insulin resistance syndrome (metabolic syndrome) and obesity in Asian Indians: evidence and implications. Nutrition 2004;20:482–491.Find this resource:

155. Jahns L, Baturin A, Popkin BM. Obesity, diet, and poverty: trends in the Russian transition to market economy. Eur J Clin Nutr 2003;57:1295–1302.Find this resource:

156. Wisdom, and Opportunity. http://www.linkedin.com/today/post/article/20130315152612-23027997-qatar-s-cultural-crisis-wealth-health-wisdom-and-opportunity?trk=mp-author-card.

157. Lands W, Hamazaki T, Yamazaki K, et al. Changing dietary patterns. Am J Clin Nutr 1990;51:991–993.Find this resource:

158. Drewnowski A, Popkin BM. The nutrition transition: new trends in the global diet. Nutrition Reviews 1997;55(2):31–43.Find this resource:

159. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States. 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed March 18, 2013.

160. Gregg EW, Cadwell BL, Cheng YJ, et al. Trends in the prevalence and ratio of diagnosed to undiagnosed diabetes according to obesity levels in the U.S. Diabetes Care 2004;27(12):2806–2812.Find this resource:

161. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. Adults. Diabetes Care 2004;27(10):2444–2449.Find this resource:

162. Reaven G, Abbasi F, McLaughlin T. Obesity, insulin resistance, and cardiovascular disease. Recent Prog Horm Res 2004;59:207–223.Find this resource:

163. World Health Organization. Diabetes Programme: Diabetes Fact Sheet. http://www.who.int/mediacentre/factsheets/fs312/en/index.html. Accessed February 28, 2013.

164. Engelgau MM, Geiss LS, Saaddine JB, et al. The evolving diabetes burden in the United States. Ann Intern Med 2004;140:945–950.Find this resource:

165. Narayan KM, Boyle JP, Thompson TJ, et al. Lifetime risk for diabetes mellitus in the United States. JAMA 2003;290(14):1884–1890.Find this resource:

166. Honeycutt AA, Boyle JP, Broglio KR, et al. A dynamic Markov model for forecasting diabetes prevalence in the United States through 2050. Health Care Manag Sci 2003;6:155–164.Find this resource:

167. Centers for Disease Control and Prevention. Diabetes Report Card, 2014. http://www.cdc.gov/diabetes/pdfs/library/diabetesreportcard2014.pdf.

168. Geiss LS, Wang J, Cheng YJ, et al. Prevalence and incidence trends for diagnosed diabetes among adults aged 20 to 79 years, United States, 1980–2012. JAMA 2014;312(12):1218–1226.Find this resource:

169. Thompson D, Wolf AM. The medical-care cost burden of obesity. Obes Rev 2001;2:189–197.Find this resource:

170. Thompson D, Edelsberg J, Colditz GA, et al. Lifetime health and economic consequences of obesity. Arch Intern Med 1999;159(18):2177–2183.Find this resource:

171. Hammond RA, Levine R. The economic impact of obesity in the United States. Diabetes Metab Syndr Obes 2010;3:285–295.Find this resource:

172. Finkelstein EA, Ruhm CJ, Kosa KM. Economic causes and consequences of obesity. Annu Rev Public Health 2005;26(1):239–257.Find this resource:

173. Finkelstein EA, Trogdon JG, Brown DS, et al. The lifetime medical cost burden of overweight and obesity: implications for obesity prevention. Obesity (Silver Spring) 2008;16(8):1843–1848.Find this resource:

174. Shamseddeen H, Getty JZ, Hamdallah IN, et al. Epidemiology and economic impact of obesity and type 2 diabetes. Surg Clin North Am 2011;91(6):1163.Find this resource:

175. Trasande L, Elbel B. The economic burden placed on healthcare systems by childhood obesity. Expert Rev Pharmacoecon Outcomes Res 2012;12(1):39–45.Find this resource:

176. Wang Y, Beydoun MA, Liang L, et al. Will all Americans become overweight or obese? estimating the progression and cost of the US obesity epidemic. Obesity 2008;16(10):2323–2330.Find this resource:

177. Withrow D, Alter DA. The economic burden of obesity worldwide: a systematic review of the direct costs of obesity. Obes Rev 2011;12(2):131–141.Find this resource:

178. Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med 2005;352(11):1138–1145.Find this resource:

179. Calle EE, Thun MJ. Obesity and cancer. Oncogene 2004;23(38):6365–6378.Find this resource:

180. Rames LK, Clarke WR, Connor WE, et al. Normal blood pressure and the evaluation of sustained blood pressure elevation in childhood: the Muscatine study. Pediatrics 1978;61(2):245–251.Find this resource:

181. Figueroa-Colon R, Franklin FA, Lee JY, et al. Prevalence of obesity with increased blood pressure in elementary school-aged children. South Med J 1997;90(8): 806–813.Find this resource:

182. Urrutia-Rojas X, Egbuchunam CU, Bae S, et al. High blood pressure in school children: prevalence and risk factors. BMC Pediatr 2006;6:32.Find this resource:

183. Sorof J, Daniels S. Obesity hypertension in children: a problem of epidemic proportions. Hypertension 2002;40(4):441–447.Find this resource:

184. Falkner B, Michel S. Obesity and other risk factors in children. Ethn Dis 1999;9(2):284–289.Find this resource:

185. Friedland O, Nemet D, Gorodnitsky N, et al. Obesity and lipid profiles in children and adolescents. J Pediatr Endocrinol Metab 2002;15(7):1011–1016.Find this resource:

186. Richards GE, Cavallo A, Meyer WJ, et al. Obesity, acanthosis nigricans, insulin resistance, and hyperandrogenemia: pediatric perspective and natural history. J Pediatr 1985;107(6):893–897.Find this resource:

187. Viner RM, Segal TY, Lichtarowicz-Krynska E, et al. Prevalence of the insulin resistance syndrome in obesity. Arch Dis Child 2005;90(1):10–14.Find this resource:

188. Friesen CA, Roberts CC. Cholelithiasis: clinical characteristics in children; case analysis and literature review. Clin Pediatr (Phila) 1989;28(7):294–298.Find this resource:

189. Kaechele V, Wabitsch M, Thiere D, et al. Prevalence of gallbladder stone disease in obese children and adolescents: influence of the degree of obesity, sex, and pubertal development. J Pediatr Gastroenterol Nutr 2006;42(1): 66–70.Find this resource:

190. Kinugasa A, Tsunamoto K, Furukawa N, et al. Fatty liver and its fibrous changes found in simple obesity of children. J Pediatr Gastroenterol Nutr 1984;3(3):408–414.Find this resource:

191. Tominaga K, Kurata JH, Chen YK, et al. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci 1995;40(9):2002–2009.Find this resource:

192. Tazawa Y, Noguchi H, Nishinomiya F, et al. Serum alanine aminotransferase activity in obese children. Acta Paediatr 1997;86(3):238–241.Find this resource:

193. Schwimmer JB, Deutsch R, Kahen T, et al. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118(4):1388.Find this resource:

194. Silvestri JM, Weese-Mayer DE, Bass MT, et al. Polysomnography in obese children with a history of sleep-associated breathing disorders. Pediatr Pulmonol 1993;16(2):124–129.Find this resource:

195. Marcus CL, Curtis S, Koerner CB, et al. Evaluation of pulmonary function and polysomnography in obese children and adolescents. Pediatr Pulmonol 1996;21(3):176–183.Find this resource:

196. Mallory GB Jr, Fiser DH, Jackson R. Sleep-associated breathing disorders in morbidly obese children and adolescents. J Pediatr 1989;115(6): 892–897.Find this resource:

197. Arens R, Muzumdar H. Childhood obesity and obstructive sleep apnea syndrome. J Appl Physiol 2010;108(2):436–444.Find this resource:

198. Tauman R, Gozal D. Obesity and obstructive sleep apnea in children. Paediatr Respir Rev 2006;7(4):247–259.Find this resource:

199. Kelsey JL. The incidence and distribution of slipped capital femoral epiphysis in Connecticut. J Chronic Dis 1971;23(8):567–578.Find this resource:

200. Kelsey JL, Acheson RM, Keggi KJ. The body build of patients with slipped capital femoral epiphysis. Am J Dis Child 1972;124(2):276–281.Find this resource:

201. Loder RT, Aronson DD, Greenfield ML. The epidemiology of bilateral slipped capital femoral epiphysis: a study of children in Michigan. J Bone Joint Surg Am 1993;75(8):1141–1147.Find this resource:

202. Wilcox PG, Weiner DS, Leighley B. Maturation factors in slipped capital femoral epiphysis. J Pediatr Orthop 1988;8(2):196–200.Find this resource:

203. Manoff EM, Banffy MB, Winell JJ. Relationship between body mass index and slipped capital femoral epiphysis. J Pediatr Orthop 2005;25(6):744–746.Find this resource:

204. Scott IU, Siatkowski RM, Eneyni M, et al. Idiopathic intracranial hypertension in children and adolescents. Am J Ophthalmol 1997;124(2):253–255.Find this resource:

205. Durcan FJ, Corbett JJ, Wall M. The incidence of pseudotumor cerebri: population studies in Iowa and Louisiana. Arch Neurol 1988;45(8):875–877.Find this resource:

206. Corbett JJ, Savino PJ, Thompson HS, et al. Visual loss in pseudotumor cerebri: follow-up of 57 patients from five to 41 years and a profile of 14 patients with permanent severe visual loss. Arch Neurol 1982;39(8):461–474.Find this resource:

207. Sugerman HJ, DeMaria EJ, Felton WL 3rd, et al. Increased intra-abdominal pressure and cardiac filling pressures in obesity-associated pseudotumor cerebri. Neurology 1997;49(2):507–511.Find this resource:

208. Balcer LJ, Liu GT, Forman S, et al. Idiopathic intracranial hypertension: relation of age and obesity in children. Neurology 1999;52(4):870–870.Find this resource:

209. Kesler A, Fattal-Valevski A. Idiopathic intracranial hypertension in the pediatric population. J Child Neurol 2002;17(10):745–748.Find this resource:

210. Willett WC, Manson JE, Stampfer MJ, et al. Weight, weight change, and coronary heart disease in women: risk within the “normal” weight range [see comments]. JAMA 1995;273(6):461–465.Find this resource:

211. Dietz WH. Childhood weight affects adult morbidity and mortality. J Nutr 1998;128(2 Suppl):411S–414S.Find this resource:

212. Srinivasan SR, Bao W, Wattigney WA, et al. Adolescent overweight is associated with adult overweight and related multiple cardiovascular risk factors: the Bogalusa Heart Study. Metabolism 1996;45(2):235–240.Find this resource:

213. Lauer RM, Clarke WR. Childhood risk factors for high adult blood pressure: the Muscatine Study. Pediatrics 1989;84(4):633–641.Find this resource:

214. Mossberg HO. 40-year follow-up of overweight children. Lancet 1989;2(8661):491–493.Find this resource:

215. Morrison JA, Glueck CJ, Horn PS, et al. Childhood predictors of adult type 2 diabetes at 9- and 26-year follow-ups. Arch Pediatr Adolesc Med 2010;164(1):53–60.Find this resource:

216. Must A, Jacques P, Dallal G, et al. Long-term morbidity and mortality of overweight adolescents. New Engl J M 1992;327(19):1350–1355.Find this resource:

217. Strauss R. Childhood obesity. Curr Prob Pediatr 1999;29(1):1–29.Find this resource:

218. Schonfeld-Warden N, Warden CH. Pediatric obesity: an overview of etiology and treatment. Pediatr Clin N Am 1997;44(2):339–361.Find this resource:

219. Lissner L, Odell P, D’Agostino R, et al. Variability of body weight and health outcomes in the Framingham population. N Engl J Med 1991;324(26):1839–1844.Find this resource:

220. Burt Solorzano CM, McCartney CR. Obesity and the pubertal transition in girls and boys. Reproduction 2010;140(3):399–410.Find this resource:

221. Brownell K. Effects of weight cycling on metabolism, health, and psychological factors. In: Brownell KD, Fairburn CG, eds. Eating Disorders and Obesity: A Comprehensive Handbook. New York, NY: Guilford; 1995:56–60.Find this resource:

222. Rzehak P, Meisinger C, Woelke G, et al. Weight change, weight cycling and mortality in the ERFORT male cohort study. Eur J Epidemiol 2007;22(10):665–673.Find this resource:

223. Taing KY, Ardern CI, Kuk JL. Effect of the timing of weight cycling during adulthood on mortality risk in overweight and obese postmenopausal women. Obesity (Silver Spring) 2012;20(2):407–4133.Find this resource:

224. Iribarren C, Sharp D, Burchfiel C, et al. Association of weight loss and weight fluctuation with mortality among Japanese American men. N Engl J Med 1995;333:686–692.Find this resource:

225. Stevens VL, Jacobs EJ, Sun J, et al. Weight cycling and mortality in a large prospective US study. Am J Epidemiol 2012;175(8):785–792.Find this resource:

226. Field AE, Malspeis S, Willett WC. Weight cycling and mortality among middle-aged or older women. Arch Intern Med 2009;169(9):881–886.Find this resource:

227. Wing R, Jeffery R, Hellerstedt W. A prospective study of effects of weight cycling on cardiovascular risk factors. Arch Intern Med 1995;155:1416–1422.Find this resource:

228. Graci S, Izzo G, Savino S, et al. Weight cycling and cardiovascular risk factors in obesity. Int J Obes Relat Metab Disord 2004;28(1):65–71.Find this resource:

229. National task force on the prevention and treatment of obesity. Weight Cycling. JAMA 1994;272(15):1196–202.Find this resource:

230. Jeffery RW. Does weight cycling present a health risk? Am J Clin Nutr 1996;63(3 Suppl):452S–455S.Find this resource:

231. Stunkard A, Sobal J. Psychosocial consequences of obesity. In: Brownell KD, Fairburn CG, eds. Eating Disorders and Obesity: A Comprehensive Handbook. New York, NY: Guilford; 1995;260–275.Find this resource:

232. Schwartz MB, Brownell KD. Obesity and body image. Body Image 2004;1(1):43–56.Find this resource:

233. Strauss RS. Childhood obesity and self-esteem. Pediatrics 2000;105(1):e15.Find this resource:

234. Petroni ML, Villanova N, Avagnina S, et al. Psychological distress in morbid obesity in relation to weight history. Obes Surg 2007;17(3):391–399.Find this resource:

235. Marchesini G, Cuzzolaro M, Mannucci E, et al. Weight cycling in treatment-seeking obese persons: data from the QUOVADIS study. Int J Obes Relat Metab Disord 2004;28(11):1456–1462.Find this resource:

236. Gortmaker SL, Must A, Perrin JM, et al. Social and economic consequences of overweight in adolescence and young adulthood. N Engl J Med 1993;329(14):1008–1012.Find this resource:

237. Puhl RM, Heuer CA. The stigma of obesity: a review and update. Obesity 2009;17(5): 941–964.Find this resource:

238. Hill J, Melanson E. Overview of the determinants of overweight and obesity: current evidence and research issues. Med Sci Sports Exerc 1999;31(11 Suppl):S515–S521.Find this resource:

239. McClure AC, Tanski SE, Kingsbury J, et al. Characteristics associated with low self-esteem among US adolescents. Acad Pediatr 2010;10(4):238–244.e2.Find this resource:

240. Griffiths LJ, Wolke D, Page AS, et al. Obesity and bullying: different effects for boys and girls. Arch Dis Child 2006;91(2):121–125.Find this resource:

241. Janssen I, Craig WM, Boyce WF, et al. Associations between overweight and obesity with bullying behaviors in school-aged children. Pediatrics 2004;113(5):1187–1194.Find this resource:

242. Thompson JW, Card-Higginson P. Arkansas’ experience: statewide surveillance and parental information on the child obesity epidemic. Pediatrics 2009;124(Suppl 1):S73–S82.Find this resource:

243. Nihiser AJ, Lee SM, Wechsler H, et al. BMI measurement in schools. Pediatrics 2009;124(Suppl 1):S89–S97.Find this resource:

244. Maddi S, Khoshaba D, Persico M, et al. Psychosocial correlates of psychopathology in a national sample of the morbidly obese. Obes Surg 1997;7:397–404.Find this resource:

245. McGinnis J, Foege. Actual causes of death in the United States. JAMA 1993;270(18):2207–2212.Find this resource:

246. Allison DB, Fontaine KR, Manson JE, et al. Annual deaths attributable to obesity in the United States. JAMA 1999;282(16):1530–1538.Find this resource:

247. Calle EE, Thun MJ, Petrelli JM, et al. Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med 1999;341(15):1097–1105.Find this resource:

248. Manson J, Willett W, Stampfer M, et al. Body weight and mortality among women. N Engl J Med 1995;333(11):677–685.Find this resource:

249. Adams KF, Schatzkin A, Harris TB, et al. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med 2006;355(8):763–778.Find this resource:

250. Flegal KM, Kit BK, Orpana H, et al. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA 2013;309(1):71–82.Find this resource:

251. Mckay B. Admitting errors, agency expected to revise findings; big health concerns remain. Wall Street Journal, 2004, A1.Find this resource:

252. Kolata G. Data on deaths from obesity is inflated, U.S. agency says. New York Times, Nov 24, 2004.Find this resource:

253. Mann CC. Public health. Provocative study says obesity may reduce U.S. life expectancy. Science 2005;307(5716):1716–1717.Find this resource:

254. Mokdad AH, Marks JS, Stroup DF, et al. Actual causes of death in the United States 2000 JAMA 2004;291(10):1238–1245.Find this resource:

255. Flegal KM, Graubard BI, Williamson DF, et al. Excess deaths associated with underweight, overweight, and obesity. JAMA 2005;293(15):1861–1867.Find this resource:

256. Ogden CL, Flegal KM, Carroll MD, et al. Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA 2002;288(14):1728–1732.Find this resource:

257. Mckay B. Doctors debate how to gauge lifestyle’s effect on mortality. Wall Street Journal, December 14, 2004, D6.Find this resource:

258. Yee D.CDC Fixes Error in Figuring Obesity Risk. Associated Press. 2005.Find this resource:

259. McKay B. CDC concedes it overstated obesity-linked deaths. Wall Street Journal, Jan 18, 2005.Find this resource:

260. Obesity death figures lowered. Reuters Health, January 18, 2005.Find this resource:

261. Obesity set “to cut US life expectancy.” Reuters, February 2, 2005.Find this resource:

262. CDC again cuts estimate of obesity-linked deaths. Associated Press, April 19, 2005.Find this resource:

263. Mark DH. Deaths attributable to obesity. JAMA 2005;293(15):1918–1919.Find this resource:

264. Gregg W, Foote A, Erfurt JC, et al. Worksite follow-up and engagement strategies for initiating health risk behavior changes. Health Educ Quart 1990;17(4):455–478.Find this resource:

265. Mokdad AH, Marks JS, Stroup DF, et al. Correction: actual causes of death in the United States, 2000. JAMA 2005;293(3):293–294.Find this resource:

266. Gregg EW, Cheng YJ, Cadwell BL, et al. Secular trends in cardiovascular disease risk factors according to body mass index in US adults. JAMA 2005;293(15):1868–1874.Find this resource:

267. Flegal KM, Williamson DF, Pamuk ER, et al. Estimating deaths attributable to obesity in the United States. Am J Public Health 2004;94(9):1486–1489.Find this resource:

268. Flegal KM, Graubard BI, Williamson DF. Methods of calculating deaths attributable to obesity. Am J Epidemiol 2004;160(4):331–338.Find this resource:

269. Centers for Disease Control and Health: dangers of being overweight overstated. Associated Press, April 19, 2005.Find this resource:

270. Kolata G. Some extra heft may be helpful, new study says. New York Times, April 20, 2005.Find this resource:

271. So is obesity bad for you or not? Reuters, April 20, 2005.Find this resource:

272. Kolata G. Why thin is fine, but thinner can kill. New York Times, April 24, 2005.Find this resource:

273. Flegal KM. Estimating the impact of obesity. Soz Praventivmed 2005;50(2):73–74.Find this resource:

274. Neergaard L. Risks jump as obesity escalates. Associated Press, 2005. Washington.Find this resource:

275. Tanner L. Experts say obesity still a health risk. Associated Press, May 1, 2005.Find this resource:

276. Koplan JP. Attempts to downplay obesity ignore dangers. Atlanta Journal-Constitution, April 29, 2005.Find this resource:

277. Couzin JA. Heavyweight battle over CDC’s obesity forecasts: how many people does obesity kill? Science 2005;5723:770–771.Find this resource:

278. Marchione M. CDC stresses obesity problem, faults study. Associated Press, June 2, 2005.Find this resource:

279. Hu FB, Willett WC, Stampfer MJ, et al. Calculating deaths attributable to obesity. Am J Public Health 2005;95(6):932; author reply, 932–933.Find this resource:

280. Flegal KM, Pamuk ER. Letter. Flegal et al. respond. Am J Public Health 2005;95(6):932–933.Find this resource:

281. Warner M. Striking back at the food police. New York Times, June 12, 2005.Find this resource:

282. JAMA News Releases. Being Obese, Underweight, Associated with Increased Risk of Death. April 19, 2005.Find this resource:

283. Masters RK, Reither EN, Powers DA, Yang YC, Burger AE, Link BG. The impact of obesity on US mortality levels: the importance of age and cohort factors in population estimates. Am J Public Health 2013;103(10):1895–1901.Find this resource:

284. Tsai AG, Williamson DF, Glick HA. Direct medical cost of overweight and obesity in the USA: a quantitative systematic review. Obes Rev 2011;12(1):50–61.Find this resource:

285. Thorpe KE, Howard DH. The rise in spending among Medicare beneficiaries: the role of chronic disease prevalence and changes in treatment intensity. Health Aff (Millwood) 2006;25(5):w378–w388.Find this resource:

286. Lightwood J, Bibbins-Domingo K, Coxson P, et al. Forecasting the future economic burden of current adolescent overweight: an estimate of the coronary heart disease policy model. Am J Public Health 2009;99(12):2230–2237.Find this resource:

287. Costello D. The price of obesity; beyond the health risks, the personal financial costs are steep, recent studies show. Los Angeles Times, August 1, 2005.Find this resource:

288. Zagorsky JL. Health and wealth: the late-20th century obesity epidemic in the U.S. Econ Hum Biol 2005;3(2):296–313.Find this resource:

289. Sturm R. The effects of obesity, smoking, and drinking on medical problems and costs. Health Aff (Millwood) 2002;21(2):245–253.Find this resource:

290. Thorpe KE, Florence CS, Howard DH, et al. The impact of obesity on rising medical spending. Health Aff (Millwood). 2004;Suppl Web Exclusives:W4-480-6.Find this resource:

291. Thorpe KE. Factors accounting for the rise in health-care spending in the United States: the role of rising disease prevalence and treatment intensity. Public Health 2006;120(11):1002–1007.Find this resource:

292. Finkelstein E, Fiebelkorn C, Wang G. The costs of obesity among full-time employees. Am J Health Promot 2005;20(1):45–51.Find this resource:

293. Rosenwald MS. Why America has to be fat: a side effect of economic expansion shows up in front. Washington Post, Jan 22, 2006, F01.Find this resource:

294. Cheap food, societal norms and the economics of obesity. Wall Street Journal online. August 25, 2006. http://online.wsj.com/public/article/SB115634907472843442-_xrNV2M1Pwf8pAcQYUWEBITP1LQ_20060901.html.

295. Close RN, Schoeller DA. The financial reality of overeating. J Am Coll Nutr 2006;25(3):203–209.Find this resource:

296. Stevens J, Kumanyika SK, Keil JE. Attitudes toward body size and dieting: differences between elderly black and white women. Am J Public Health 1994;84:1322–1325.Find this resource:

297. Caldwell MB, Brownell KD, Wilfley DE. Relationship of weight, body dissatisfaction, and self-esteem in African American and white female dieters. Int J Eat Disord 1997;22(2):127–130.Find this resource:

298. Neff LJ, Sargent RG, McKeown RE. Black-white differences in body size perceptions and weight management practices among adolescent females. J Adolesc Health 1997;20:459–465.Find this resource:

299. Thompson SH, Sargent RG. Black and White women’s weight-related attitudes and parental criticism of their childhood appearance. Women Health 2000;30:77–92.Find this resource:

300. Anderson LA, Eyler AA, Galuska DA, et al. Relationship of satisfaction with body size and trying to lose weight in a national survey of overweight and obese women aged 40 and older, United States. Prev Med 2002;35:390–396.Find this resource:

301. Perez M, Joiner TE Jr. Body image dissatisfaction and disordered eating in black and white women. Int J Eat Disord 2003;33:342–350.Find this resource:

302. Akan GE, Grilo CM. Sociocultural influences on eating attitudes and behaviors, body image, and psychological functioning: a comparison of African-American, Asian-American, and Caucasian college women. Int J Eat Disord 1995;18:181–187.Find this resource:

303. Ashworth M, Clement S, Wright M. Demand, appropriateness and prescribing of “lifestyle drugs”: a consultation survey in general practice. Fam Pract 2002;19:236–241.Find this resource:

304. Lexchin J. Lifestyle drugs: issues for debate. CMAJ 2001;164:1449–1451.Find this resource:

305. Mitka M. Surgery for obesity: demand soars amid scientific, ethical questions. JAMA 2003;289:1761–1762.Find this resource:

306. Puhl R, Brownell KD. Ways of coping with obesity stigma: review and conceptual analysis. Eat Behav 2003;4:53–78.Find this resource:

307. Puhl RM, Brownell KD. Psychosocial origins of obesity stigma: toward changing a powerful and pervasive bias. Obes Rev 2003;4:213–227.Find this resource:

308. Latner JD, Stunkard AJ. Getting worse: the stigmatization of obese children. Obes Res 2003;11:452–456.Find this resource:

309. Kappagoda CT, Hyson DA, Amsterdam EA. Low-carbohydrate-high-protein diets: is there a place for them in clinical cardiology? J Am Coll Cardiol 2004;43:725–730.Find this resource:

310. Kong A, Beresford SA, Alfano CM, et al. Associations between snacking and weight loss and nutrient intake among postmenopausal overweight to obese women in a dietary weight-loss intervention. J Am Diet Assoc 2011;111:1898–1903.Find this resource:

311. Jenkins D, Wolever T, Vuksan V, et al. Nibbling versus gorging: metabolic advantages of increased meal fequency. N Engl J Med 1989;321:929–934.Find this resource:

312. Speechly D, Rogers G, Buffenstein R. Acute appetite reduction associated with an increased frequency of eating in obese males. Int J Obes Relat Metab Disord 1999;23:1151–1159.Find this resource:

313. Bellisle F, McDevitt R, Prentice A. Meal frequency and energy balance. Br J Nutr 1997;77(Suppl 1):s57–s70.Find this resource:

314. Drummond S, Crombie N, Kirk T. A critique of the effects of snacking on body weight status. Eur J Clin Nutr 1996;50:779–783.Find this resource:

315. Fox K. The influence of physical activity on mental well-being. Public Health Nutr 1999;2:411–418.Find this resource:

316. Miller W, Koceja D, Hamilton E. A meta-analysis of the past 25 years of weight loss research using diet, exercise or diet plus exercise intervention. Int J Obes Relat Metab Disord 1997;21(10):941–947.Find this resource:

317. US Preventive Services Task Force. Behavioral Counseling in Primary Care to Promote a Healthy Diet. Recommendations and Rationale. Guide to Clinical Preventive Services. 2nd ed. Washington, DC: Office of Disease Prevention and Health Promotion; 1996.Find this resource:

318. Moyer VA. Behavioral counseling interventions to promote a healthful diet and physical activity for cardiovascular disease prevention in adults: a US Preventive Services Task Force Recommendation Statement. Ann Intern Med 2012;157:367–372.Find this resource:

319. US Preventive Services Task Force. Screening and Interventions to Prevent Obesity in Adults. 2003. http://www.ahrq.gov/clinic/uspstf/uspsobes.htm. Accessed March 18, 2007.

320. Lin JS, O’Connor E, Whitlock EP, et al. Behavioral counseling to promote physical activity and a healthful diet to prevent cardiovascular disease in adults: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2010;153:736–750.Find this resource:

321. Ockene I, Hebert J, Ockene J, et al. Effect of physician-delivered nutrition counseling training and an office-support program on saturated fat intake, weight, and serum lipid measurements in a hyperlipidemic population: Worcester Area Trial for Counseling in Hyperlipidemia (WATCH). Arch Intern Med 1999;159:725–731.Find this resource:

322. Long BJ, Calfas KJ, Wooten W, et al. A multisite field test of the acceptability of physical activity counseling in primary care: project PACE. Am J Prev Med 1996;12(2):73–81.Find this resource:

323. Blackburn DG. Establishing an effective framework for physical activity counseling in primary care settings. Nutr Clin Care 2002;5(3):95–102.Find this resource:

324. Albright CL, Cohen S, Gibbons L, et al. Incorporating physical activity advice into primary care: physician-delivered advice within the activity counseling trial. Am J Prev Med 2000;18(3):225–234.Find this resource:

325. Kerse N, Elley CR, Robinson E, et al. Is physical activity counseling effective for older people? A cluster randomized, controlled trial in primary care. J Am Geriatr Soc 2005;53(11):1951–1956.Find this resource:

326. Petrella RJ, Koval JJ, Cunningham DA, et al. Can primary care doctors prescribe exercise to improve fitness? The Step Test Exercise Prescription (STEP) project. Am J Prev Med 2003;24(4):316–322.Find this resource:

327. Nawaz H, Adams M, Katz D. Weight loss counseling by health care providers. Am J Public Health 1999;89:764–767.Find this resource:

328. Tham M, Young D. The role of the general practitioner in weight management in primary care- a cross sectional study in general practice. BMC Fam Pract 2008;9:66.Find this resource:

329. Biener L, Heaton A. Women dieters of normal weight: their motives, goals, and risks. Am J Public Health 1995;85:714–717.Find this resource:

330. Nawaz H, Katz D, Adams M. Physician-patient interactions regarding diet, exercise and smoking. Prev Med 2000;31:652–657.Find this resource:

331. Wieland LS, Falzon L, Sciamanna CN, et al. Interactive computer-based interventions for weight loss or weight maintenance in overweight or obese people. Cochrane Database Syst Rev 2012;8:CD007675.Find this resource:

332. Spring B, Duncan JM, Janke EA, et al. Integrating technology into standard weight loss treatment: a randomized controlled trial. JAMA Intern Med 2013;173(2):105–111.Find this resource:

333.Accelerating Progress in Obesity Prevention. 2012. http://www.iom.edu/Reports/2012/Accelerating-Progress-in-Obesity-Prevention.aspx.

334. Wing RR, Jeffery RW. Food provision as a strategy to promote weight loss. Obes Res 2001;9:271S–275S.Find this resource:

335. Jeffery RW, Wing RR. Long-term effects of interventions for weight loss using food provision and monetary incentives. J Consult Clin Psychol 1995;63:793–796.Find this resource:

336. Rapoport L, Clark M, Wardle J. Evaluation of a modified cognitive-behavioural programme for weight management. Int J Obes Relat Metab Disord 2000;24(12):1726–1737.Find this resource:

337. Harvey-Berino J. The efficacy of dietary fat vs. total energy restriction for weight loss. Obes Res 1998;6:202–207.Find this resource:

338. Epstein LH. Family-based behavioural intervention for obese children. Int J Obes Relat Metab Disord 1996;20(Suppl 1):S14–S21.Find this resource:

339. Torgerson JS, Lissner L, Lindroos AK, et al. VLCD plus dietary and behavioural support versus support alone in the treatment of severe obesity: a randomised two-year clinical trial. Int J Obes Relat Metab Disord 1997;21(11):987–994.Find this resource:

340. Wadden T, Foster G, Letizia K. One-year behavioral treatment of obesity: comparison of moderate and severe caloric restriction and the effects of weight maintenance therapy. J Consult Clin Psychol 1994;62(1):165–171.Find this resource:

341. Buettner D.The Blue Zones. Washington, DC: National Geographic; 2008.Find this resource:

342. Welch HG, Schwartz L, Woloshin S. What’s making us sick is an epidemic of diagnoses, New York Times, January 2, 2007.Find this resource:

343. The Affordable Care Act. Available from: https://www.healthcare.gov/.

344. Preventive Medicine Research Institute. Ornish Programs Reimbursed by Medicare. http://www.pmri.org/certified_programs.html. Accessed February 6, 2014.

345. Katz DL. Eat and run blog: school over scalpels. US News & World Report. 2013. http://health.usnews.com/health-news/blogs/eat-run/2013/01/11/school-over-scalpels.

346. Katz DL. Are our children “diseased”? Childhood Obesity 2014;10(1):1–3.Find this resource:

347. Galvez MP, Pearl M, Yen IH. Childhood obesity and the built environment. Curr Opin Pediatr 2010;22(2):202–207.Find this resource:

348. Friedman RR, Schwartz MB. Public policy to prevent childhood obesity, and the role of pediatric endocrinologists. J Pediatr Endocrinol Metab 2008;21(8):717–125.Find this resource:

349. Bleich SN, Segal J, Wu Y, Wilson R, Wang Y. Systematic review of community-based childhood obesity prevention studies. Pediatrics 2013;132(1):e201–e210.Find this resource:

350.Online Weight Management Counseling for Healthcare Providers. http://www.turnthetidefoundation.org/OWCH/index.htm.

351.Weigh Forward. http://www.rediclinic.com/weighforward/. Accessed February 7, 2014.