Obesity is now so common within the world's population that it is beginning to replace undernutrition and infectious diseases as the most significant contributor to ill health. In particular, obesity is associated with diabetes mellitus, coronary heart disease, certain forms of cancer, and sleep-breathing disorders. Obesity is defined by a body-mass index (weight divided by square of the height) of 30 kg m(-2) or greater, but this does not take into account the morbidity and mortality associated with more modest degrees of overweight, nor the detrimental effect of intra-abdominal fat. The global epidemic of obesity results from a combination of genetic susceptibility, increased availability of high-energy foods and decreased requirement for physical activity in modern society. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals, but an epidemic that threatens global well being.

Obesity as a medical problem

Background Studies in animals indicate that brown adipose tissue is important in the regulation of body weight, and it is possible that individual variation in adaptive thermogenesis can be attributed to variations in the amount or activity of brown adipose tissue. Until recently, the presence of brown adipose tissue was thought to be relevant only in small mammals and infants, with negligible physiologic relevance in adult humans. We performed a systematic examination of the presence, distribution, and activity of brown adipose tissue in lean and obese men during exposure to cold temperature. Brown-adipose-tissue activity was studied in relation to body composition and energy metabolism. Methods We studied 24 healthy men — 10 who were lean (body-mass index [BMI] [the weight in kilograms divided by the square of the height in meters], <25) and 14 who were overweight or obese (BMI, ≥25) — under thermoneutral conditions (22°C) and during mild cold exposure (16°C). Putative brown-adipose-tissue activity was ...

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Cold-activated brown adipose tissue in healthy men.

Adjustment for total energy intake in epidemiologic studies

Obesity results when energy intake exceeds energy expenditure Naturally occurring genetic mutations, as well as ablative lesions, have shown that the brain regulates both aspects of energy balance and that abnormalities in energy expenditure contribute to the development of obesity Energy can be expended by performing work or producing heat (thermogenesis) Adaptive thermogenesis, or the regulated production of heat, is influenced by environmental temperature and diet Mitochondria, the organelles that convert food to carbon dioxide, water and ATP, are fundamental in mediating effects on energy dissipation Recently, there have been significant advances in understanding the molecular regulation of energy expenditure in mitochondria and the mechanisms of transcriptional control of mitochondrial genes Here we explore these developments in relation to classical physiological views of adaptive thermogenesis

Towards a molecular understanding of adaptive thermogenesis.

Readers of this journal do not need to be reminded of the explosive increase in obesity/type 2 diabetes syndromes and their attendant staggering public health costs that are currently afflicting developed countries. Because of this alarming development and what it portends for the future if left unchecked, the American Diabetes Association, together with its counterparts around the world, as well as the World Health Organization, are faced with the daunting challenge of finding answers to two huge questions. First, what is the pathophysiological basis for these disorders? Second, why is their rate of appearance accelerating so rapidly at this particular juncture of human history, and what, if anything, can we do to intervene? The primary focus of this lecture will be on the first of these issues. I want to emphasize at the outset that I do not plan to dwell exclusively on our own studies in this area. Instead, I shall try to incorporate recent developments from a variety of other laboratories working in the field. Although these will of necessity have to be highly selective, I hope that collectively they will illustrate how we have come to a relatively new and exciting way of thinking about the etiology of type 2 diabetes.

It has been said in literary circles that James Joyce’s Ulysses is probably the most frequently opened and least read book that has ever been published. In a similar vein, I sometimes think that the question of what causes type 2 diabetes might be one of the most frequently asked and least satisfactorily answered in the history of diabetes research. This is not meant to be an arrogant statement, nor indeed does it imply that I have a magical solution to the question at hand. Rather, it simply reflects the fact that at the dawn of …

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Banting Lecture 2001: Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes

The contribution of reduced energy expenditure to the development of obesity has been a point of controversy. We measured 24-hour energy expenditure (adjusted for body composition, age, and sex), in a respiratory chamber, in 95 southwestern American Indians. Energy expenditure correlated with the rate of change in body weight over a two-year follow-up period (r = -0.39, P less than 0.001). The estimated risk of gaining more than 7.5 kg in body weight was increased fourfold in persons with a low adjusted 24-hour energy expenditure (200 kcal per day below predicted values) as compared with persons with a high 24-hour energy expenditure (200 kcal per day above predicted values; P less than 0.01). In another 126 subjects, the adjusted metabolic rate at rest at the initial visit was also found to predict the gain in body weight over a four-year follow-up period. When the 15 subjects who gained more than 10 kg were compared with the remaining 111 subjects, the initial mean (+/- SD) adjusted metabolic rate at rest was lower in those who gained weight (1694 +/- 103 vs. 1764 +/- 109 kcal per day; P less than 0.02) and increased to 1813 +/- 134 kcal per day (P less than 0.01) after a mean weight gain of 15.7 +/- 5.7 kg. In a group of 94 siblings from 36 families, values for adjusted 24-hour energy expenditure aggregated in families (intraclass correlation = 0.48). We conclude that a low rate of energy expenditure may contribute to the aggregation of obesity in families.

Reduced Rate of Energy Expenditure as a Risk Factor for Body-Weight Gain

The transition from a high carbohydrate to a high fat diet may explain in part the dramatic increase in the prevalence of noninsulin-dependent diabetes mellitus among Pima Indians over the last century In this study, 12 Pimas and 12 caucasians, all nondiabetic, were admitted to a metabolic ward and, in random order, fed 2 14-day weight-maintaining diets: a traditional Pima diet (percentage of calories: carbohydrate, 70% fat, 15%; protein, 15%) and a high fat modern diet (carbohydrate, 30%; fat, 50%; protein, 20%) Carbohydrate metabolism was characterized using the modified iv glucose tolerance test (minimal model), the acute insulin responses to arginine during a 3-step glycemic clamp, and the oral glucose tolerance test Compared with the traditional diet, the modern diet was associated with a decrease in oral glucose tolerance (P less than 001) and higher plasma cholesterol concentrations (P less than 002) The decline in glucose tolerance was associated with similar insulin-mediated, but 23% lower glucose-mediated (P less than 0001), glucose disposal, a 17% lower acute insulin response to glucose (P less than 003), a 9% lower beta-cell sensitivity to glucose (P less than 002), and similar beta-cell capacities Pimas and caucasians responded similarly, except for larger changes in plasma lipids among the Pimas Since glucose-mediated glucose disposal, beta-cell function, and glucose tolerance deteriorated on the modern diet, it is likely that diet composition affects the prevalence of noninsulin-dependent diabetes mellitus in both Pimas and caucasians

Deterioration in carbohydrate metabolism and lipoprotein changes induced by modern, high fat diet in Pima Indians and Caucasians.

Energy balance (energy intake-energy expenditure) is known to vary considerably on a day-to-day basis in free-living individuals. The extent to which stores of protein, carbohydrate, and fat are used to store short-term surpluses of energy and the extent to which these stores are used to make up temporary energy deficits are incompletely known. We have measured body energy balance as well as carbohydrate, fat, and protein balances in 27 Caucasian men and 27 Caucasian women over a 24-h period in a respiratory chamber. An estimated weight-maintenance diet was fed to each subject. Because of individual differences in family background, body composition, activity, and the failure of some subjects to eat all of their food, these estimates are not exact, and energy balance is rarely achieved. Energy balance was correlated with fat balance in men (r = 0.79, P less than 0.0001) and women (r = 0.72, P less than 0.0001), and the slope of this relationship was not distinguishable from unity in men (1.16 +/- 0.18) or women (0.80 +/- 0.15). There were no correlations between energy balance and either carbohydrate or protein balances. This study demonstrates that carbohydrate and protein stores are closely regulated by adjusting oxidation to intake. Thus fat, rather than carbohydrate or protein, is almost exclusively used or stored in response to day-to-day fluctuations in energy balance.

Short-term energy balance: relationship with protein, carbohydrate, and fat balances.

Energy cost of physical activity on a metabolic ward in relationship to obesity.

OBJECTIVE— To examine changes in the Pima Indian diet composition that may have played a role in the dramatic rise in the incidence of NIDDM among Pima Indians over the last century. RESEARCH DESIGN AND METHODS— We investigated the composition of the foods comparable to those available to the Pima ∼ 100 yr ago, with the aim of reproducing this traditional diet as faithfully as possible for a dietary intervention study. An approximation of the traditional diet was ascertained from the ethnohistoric literature and traditional recipes. RESULTS— We estimated that the traditional Pima diet, although seasonably variable, was ∼ 70–80% carbohydrate, 8–12% fat, and 12–18% protein. A diet analogous to the traditional Pima diet is largely reproducible with the foods available today. Many native foods are available locally and many commercial products can be substituted when native foods are unavailable. CONCLUSIONS— The Pima Indian diet of the last century was much higher in carbohydrate and lower in fat compared with the modern-day Pima diet. Any changes that this diabetes-prone population can make toward their traditional diet may help to decrease their incidence of diabetes.

Vicky L Boyce

Papers

Reduced Rate of Energy Expenditure as a Risk Factor for Body-Weight Gain

Deterioration in carbohydrate metabolism and lipoprotein changes induced by modern, high fat diet in Pima Indians and Caucasians.

Short-term energy balance: relationship with protein, carbohydrate, and fat balances.

Energy cost of physical activity on a metabolic ward in relationship to obesity.

The traditional Pima Indian diet : composition and adaptation for use in a dietary intervention study