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“Globally, a billion people are obese,” reports the New York Times. “In the United States, about 60 percent of adults are overweight or obese, as are nearly 13 percent of children. Some 300,000 Americans a year die from illnesses caused or exacerbated by obesity.”1 Newsstands never lack for headlines announcing new diets and drugs to counter the hazards of obesity, but the magazine rack is lined with publications advertising a superabundance of tempting foods. The diet of our great grandparents might have featured a couple of hundred different items during the year; the modern supermarket puts at our ﬁngertips thousands of fresh foods from every corner of the earth. We are urged to purchase every delicacy and bring every new labor-saving device into our homes, but warned, at the same time, to become more physically active and to eat with greater restraint.
It seems plausible to blame the high prevalence of obesity on this changed environment, which, at every turn, seems to favor the storage rather than the expenditure of calories. Still, most of us persist in ﬁnding the fault in human frailty. A recent letter to the Wall Street Journal asked, “What happened to the human will?… a will to stay thin must come from some motivation…few people in this country have sufﬁcient inner motivation to become and stay thin, in deﬁance of overwhelming cultural forces to the contrary…human nature, and the nature of human eating behavior, will trump any diet plan eventually.”2
While so many of us have viewed obesity as a drama of temptation versus discipline, scientists have responded to the epidemic with a steady stream of publications on the nature of obesity and basic biological mechanisms that may be at fault. A recent computer search for scientiﬁc articles on obesity unearthed 48,481 entries since 1966, including 2,444 just in the ﬁrst half of 2002. They comprise roughly 40 percent of all scientiﬁc reports on health problems of wide public concern, such as cancer, heart disease, and AIDS.
This research has revealed a biochemical system in both experimental animals and humans that is efﬁcient at storing calories and preventing starvation. Hormones have been identiﬁed that control food intake and energy expenditure. It has become reasonably clear in experimental animals that genetic endowment can lead to marked obesity, and that human obesity is an inheritable disorder. Can self-discipline alone override the genetic and biochemical systems described in the scientiﬁc literature?
Some years ago, after a lecture to medical students in which I emphasized how molecular biology was deepening our understanding of energy metabolism and obesity in humans, and summarized evidence that the level of fat storage is determined by genes and molecules, a student asked me if I believed in “free will.” That unexpected question led me to urge him to examine the problem of obesity and food intake behavior ﬁrst with scientiﬁc observations and hypotheses, which are simpler than the complex philosophic considerations that surround the concept of free will. I urge the reader to do the same, joining me in a brief review of what is known about obesity before I revisit the question of free will.
How to Eat 14 Tons of Food Without Gaining Weight
Obesity is an excessive storage of fat, beyond the 10 to 15 percent of body weight that is considered normal. The material stored in adipose tissue is triglyceride, an energy-rich fat containing nine calories per gram as compared with four calories per gram of protein or carbohydrate. Triglyceride is broken down to fatty acids for transport to muscle and other energy-requiring sites by a series of chemical steps that are exquisitely sensitive to our nutritional state as well as to our momentary needs for energy in situations of fear or arousal. The storage of triglyceride is accomplished by a reversal of the steps that occur in this breakdown; fatty acids ingested or synthesized from dietary carbohydrate can be readily stored as adipose tissue triglyceride.
Measuring obesity by body weight alone can be misleading. A better method is Body Mass Index (BMI), which is a person’s weight divided by the square of his body height in inches times 703. A BMI greater than 25 is considered overweight and greater than 30 is obese.
Over the long haul, our level of fat storage ﬂuctuates amazingly little. In a lifetime, an individual may consume 70 million calories—about 14 tons of food—and expend the same number of calories to produce body heat and engage in physical activity. The relative constancy of our body composition in the face of this enormous ﬂow-through of calories is shown in the illustration. The coupling of food intake with utilization of energy (burning calories) to maintain a virtually steady state does not occur by chance: It is ensured by a remarkably accurate system of controls. A persistent error in this system of as little as one percent would lead to either gargantuan obesity or wasting away.
We do not understand exactly how our bodies achieve this balance, but one thing is certain: No explanation is acceptable that violates fundamental scientiﬁc laws. Vitalism, which invokes explanations outside physical or chemical forces for the way living creatures produce heat and work, suffered a great setback at the end of the 18th century with the discoveries of Antoine Lavoisier, a founder of modern chemistry. In New York’s Metropolitan Museum of Art, at the head of a grand staircase, hangs a large, brilliantly colored painting by Jacques-Louis David portraying Lavoisier and his wife at a table crowded with glass retorts and various instruments. In this workshop for the measurement of gases, Lavoisier dealt a fatal blow to Vitalism and, by implication, all explanations of obesity that seek to ignore thermodynamics, the science of calories and energy. He proved that the production of heat in animal systems follows the same chemical steps as the burning of wood or other fuel. Whatever behaviors govern how we eat, our bodies deal with all we eat according to the laws of thermodynamics; energy that we store as fat must be the difference between what is taken in and what is expended as heat and work.
Lavoisier’s life was tragically ended in a guillotine of the French Revolution, but 150 years later, at the University of Michigan, L. H. Newburgh did experiments proving Lavoisier’s observations true for all humans, obese or not.3 No exception has been found to the rule that reducing caloric intake leads to a decline in the storage of fat. When we consume a calorie-reduced diet, there may be ﬂuctuations in our body weight that over brief periods appear to violate known laws of thermodynamics, but these ﬂuctuations turn out to be the result of transient shifts in body ﬂuids. One simply cannot invoke exceptions to the laws of thermodynamics to either explain or treat obesity. Nevertheless, to this day nostrums, fad diets, and drugs are routinely proposed to “melt away fat.”
Fat Rats and Bad Habits
In 1948, when I began my medical career, the ofﬁcial nomenclature used in medical records divided obesity into two types: endogenous and exogenous. Endogenous obesity was thought to be caused by some internal aberration in the mechanism for storing calories, while exogenous obesity was thought to be driven by food choice and lack of physical activity. People often referred to an obese person’s problem as “glandular,” whereas, by implication, another obese person simply ate too much. Newburgh championed a different view, writing that “we wish to commit ourselves to the statement that obesity is never directly caused by abnormal metabolism, but that it is always due to food habits not adjusted to the metabolic requirement— either the ingestion of more food than is normally needed or the failure to reduce the intake in response to a lowered requirement.” Newburgh was underscoring the inviolability of caloric arithmetic. For fat stores to enlarge, the intake of calories must exceed the outgo. In this sense, obesity is always exogenous. This truth has been used to lay blame on our choices and behaviors as the sole causes and full explanation for obesity.
Ten years after Newburgh’s work, an experiment was reported that gave pause to all who believe that obesity is fully explained by human caprice and sloth. If a speciﬁc portion of a rat’s brain, the ventromedial area of the hypothalamus, is destroyed, the rat becomes hugely obese.4 Unless prevented, these rats eat so ravenously immediately after surgery that their stomachs can rupture. At three to ﬁve times the weight of control animals that have had a sham operation, these monstrously large creatures barely waddle around their cages. Here, at last, appeared to be the determining factor in food intake: a neural control center. When this center was destroyed, removing its braking force, food intake increased hugely. The consequence was obesity.
As scientists studied this arresting experimental obesity, they learned that after the rats with the brain lesions had achieved a high level of fat storage and body weight, their eating slowed; they maintained their new, high weight but did not increase it. If starved brieﬂy, however, so that they lost weight, they would defend their post-surgery weight by overeating again. Another clue was that fattening an animal before brain surgery markedly reduced the high level of food intake after the surgery. The animals seemed to be overeating after the surgery only to reach a speciﬁc new level of fat storage ordained by the brain damage. It seems that food intake behavior is important, but only as a means of altering levels of fat storage that are called for by the brain mechanisms that dictate the level of that storage.
This has been called the set-point theory of obesity. To some, it contradicts the supposedly obvious idea that obese people are driven by hedonistic pleasure in eating. I can only say that scientiﬁc inquiry sometimes ﬁnds truth that initially offends common sense. (How obvious to common sense is the extremely rapid rotation of the earth on its axis?)
Although the experiments with a hypothalamic set point were with rats, earlier clinical observations had shown the importance of hypothalamic function in humans, as well. Certain rare brain tumors, and also encephalitis impinging on the hypothalamus, can lead to the sudden onset of overeating and obesity in humans. For many years, the research revealing that the operation of these neural centers was closely coupled to fat storage was largely ignored; most believed that whatever role these neural centers played in human obesity, the central issue and the roots of obesity remained psychologic aberrations or bad habits. Behavior, more easily observed than alterations in the hypothalamus, was still seen as the villain.
Psychoanalysts explored the symbolic importance of food and eating in the conscious and unconscious realms of their obese patients. One psychiatrist favored the concept that some parents used food inappropriately to reward infants and children, so that eating became a psychological symbol of pleasure or comfort, rather than a response to the normal physiologic need for calories. Studies in animals and humans were reported that examined whether eating was for “taste” or for “calories.” Psychologists and sociologists theorized that obese subjects were less attuned to internal signals for food intake than to external events that drove them to the obese state.5 Perhaps, it was suggested, they did not appropriately sense gastric contractions or emptiness, but were driven to overeat by the attractiveness or good taste of food. These studies became central in the development of behavioral modiﬁcation as a treatment for obesity.
Brain Trumps Behavior
After World War II, rising rates of heart disease and diabetes drew attention to obesity as a risk factor for illness. Scientists at the University of Vermont proposed to induce obesity experimentally in humans to see how it might change human chemistry to provoke diabetes or heart disease. Surely urging people to eat an abundance of tasty foods and avoid physical effort would make them obese. Were such behaviors not common among Americans? For their experiment, the scientists recruited a captive population: inmates in a state penitentiary who—with full understanding of the experimental goals and nature of the study—eagerly volunteered to get fat. Although some volunteers gained weight, it was extremely difﬁcult for them to become signiﬁcantly obese. The few who did so, quickly and spontaneously lost the weight they had gained. Apparently, one’s usual lean weight resisted change.
If people who are lean cannot readily be made obese, is it surprising that people who are obese will resist change, as well?
My work on obesity has been shaped by the discovery that fat storage is tightly controlled by a biological system that may have evolved to protect us from starvation. This system must have a means of sensing a body’s level of fat storage and also a means of inﬂuencing eating behavior and metabolism. I wondered if the nature of this regulatory system could be clariﬁed by comparing the metabolism and behavior of obese individuals before and after weight loss. Working with obese patients at Rockefeller University Hospital, my colleagues and I found that patients in their obese state had no speciﬁc constellation of behavioral abnormalities or psychologic aberrations; nothing convincingly implicated any psychiatric or psychologic disturbance as the cause of their obesity.
After these same patients lost weight, however, they manifested many behavioral and physiological alterations.6 They developed a marked preoccupation with food and dieting; and their physical and mental activity generally slowed down.7 Changes in our patients’ perception of the passage of time suggested that an internal clock had slowed.8 Their body image also became distorted. Weight-reduced patients who viewed photographs of themselves, and could “correct” their dimensions by means of a lens that distorted the image they observed, restored their thinned image to a larger one: their former obese state.9 Other physical signs and symptoms included slowing of heart rate, reduction of white blood cell count, intolerance to cold, and cessation of menstruation—all similar to the effects of starvation. To all appearances, our weight-reduced patients were experiencing starvation, although the level of caloric storage in adipose tissue had been reduced only to a supposedly normal level.
On still closer examination, the changes in the cells of their adipose tissue conﬁrmed my suspicion that weight reduction had not restored them to some “normal” state. The fat cells of obese individuals differed in two crucial ways from the fat cells of people of normal weight who had never been obese. The obese patients had a greater number of fat cells and each cell stored more triglyceride than the non-obese individual’s cell. When the obese lost weight, decreasing fat storage, their fat cells shrank but the number of fat cells did not change.
Most fat cells are laid down early in life. With starvation and emptying of the cells in adult life, the number of cells does not decrease. In mild obesity, cells may be enlarged without increasing in number, but with more serious levels of obesity, the number of cells is always increased. At exactly what stage the number of cells in the body increases has not yet been established. The discovery of a persistently increased number of fat cells even after weight reduction led to this hypothesis about how the brain might control eating behavior: Perhaps changes in adipose tissue (cell size, cell number, or both) were being detected and relayed in some way to the brain.
Using the new techniques of molecular biology, we have learned that hormones such as leptin, derived from adipose tissue, increase or decrease in amount as adipose tissue mass (and hence fat-cell size) alters. By means of these hormonal changes, levels of fat storage are conveyed to the brain, leading to modulation of food intake and energy production. Strains of mice and rats with defects in either the synthesis or secretion of leptin or in its detection by the brain become markedly and persistently obese, but very few obese humans have these genetic defects in leptin secretion or detection; in fact, they usually have a superabundance of leptin. Animal studies that include analysis of spontaneously occurring gene mutation and experimentally induced gene “knockouts” show the importance of several peptides in the control of fat storage: neuropeptide Y, cholecystokinin, melanocortin, and agouti-signaling protein. There are regular additions to this list, attesting to the complexity of the control of food intake at the hypothalamic level. Abnormalities in the production or detection of any of these peptides remains a rare cause for human obesity, however, and controlling their levels has not been shown to cure obesity.
Because the system is harder to probe in humans than experimental animals, we took another tack. We studied the balance, or equilibrium, of food intake, storage, and energy dissipation in humans, particularly during the state of quasi-starvation that occurs after weight reduction. Examining obese patients hospitalized in the clinical research center of the Rockefeller University Hospital, we ascertained how many excess fat calories they had stored, then divided by the number of days and years it took them to gain their excess weight.
What is striking is that the additional amount that must have been eaten per day to produce obesity, compared with what was needed to maintain body weight, was not very great. Apparently, a few bites more or less per day can make one either obese or lean. Moreover, measuring food intake in obese and non-obese individuals at their usual levels of physical activity reveals that once people achieve their obese level, they do not “overeat” to continue weight gain; they eat appropriately for their new body size.
The body weight of an obese or nonobese person tends to remain constant. When the system for controlling fat storage is challenged by experimental over- or under-feeding, energy expenditure alters as a counter force “bucking” the change. The overfed person increases fat storage but burns more calories, which acts as a brake on further accumulation of fat mass. The reverse occurs with weight reduction; a decline in body fat storage leads to a decrease in the burning of calories.10 Although we have seen this regulation of caloric expenditure to maintain a “usual” level of fat storage, whether lean or obese, in every subject (more than 50) studied over recent years, we still cannot be certain that it occurs in every obese person forever, regardless of effort to lose or gain weight.
As body fat stores shrink or enlarge, the compensating changes in energy expenditure may amount to 15 to 20 percent of one’s usual caloric intake. In bygone ages, this automatic regulation of the burning of calories may have protected caloric reserves when food was scarce. With today’s abundance of food, however, we can more easily control fat storage by how much we eat than how much energy we expend. An individual can easily double or halve dietary intake, inducing rapid changes in caloric balance, which is almost impossible to achieve by any alterations in physical activity. Nevertheless, the smaller changes that we observe in energy expenditure when we change storage by experimental force feeding or under feeding can be considered “markers” for the complex control system of fat storage. Among the components of this control system, the behavior of food intake has a prominent role.
Thus we see that a behavior usually ascribed to subtle psychologic mechanisms is profoundly affected by an internal biological system that regulates storage of body fat. This system resists dieting or other attempts to reduce the large fat accumulation typical of an obese person. I have learned that this conclusion is hard for many people to accept. Eating is so much a part of our daily lives that it is difﬁcult to believe that our choices of food, both in type and quantity, are the result at least in part of an impersonal regulatory system instead of our own “bad” behaviors. When we eat our way back to obesity after weight loss we punitively label it recidivism.
The Roots of Obesity in Infancy
The truly relevant question is not why obese people fail treatment; it is how their level of fat storage became elevated and then regulated at a high and unhealthful level. When and how is this neural regulatory system, with its associated behaviors, formed and put in action? We know enough now to venture some good guesses.
Obesity is probably rooted in infancy and childhood, when strong genetic determinants are shaping a still-plastic organism. Unquestionably, American prosperity has made possible an environment that is outstandingly successful in promoting growth. Recent generations of Americans are not only taller than their forebears, but develop faster—as evidenced, in women, by the earlier onset of menstruation.
Animal experiments show that early nutrition is pivotal. Adult rats purposely overfed or semi-starved have predictable increases or decreases in their fat storage, but the changes are rapidly eliminated when the animal resumes feeding at will. If, however, the nutritional intervention is done in the earliest weeks of life, the effect is long lasting.11 For the remainder of its life, the rat over or underfed as a pup will have an altered body size and fat storage. Thus, early overfeeding makes for a persistently larger adult rat, which stores more fat than its underfed brothers. This is reﬂected in the number of fat cells. There are a large number of fat cells in a larger animal; the size of cells, however, is unchanged by the infantile experience. Apparently, early nutrition events are powerful enough to make major changes in the way the individual’s genes inﬂuence fat storage. An animal experiment illuminates this nature-nurture interaction. The Zucker obese rat is a genetically obese strain, but a given rat’s fatness in adult life will be reduced by roughly 50 percent if the rat is brieﬂy underfed in infancy.12 In adult life, a similar brief fast produces only transient weight loss.
Does this occur in humans, as well? Our long, gradual development as infants and children, which scientists call neoteny, offers abundant time for alterations in food intake and physical activity, as well as illnesses and other events, that might inﬂuence growth and development. The individual’s neural apparatus for fat control is “set” as genetic endowment and experience combine to shape development, including behaviors related to our acquisition of food and our attachment of complex symbolism and meanings to eating. As these are inscribed in the developing cerebral cortex, the hypothalamic/adipose-tissue regulatory circuit remains a basic foundation for controlling food intake and calorie expenditure. With time, however, the hypothalamic system is joined by other control systems that are more widely distributed in the cerebrum. It is not surprising that searching the molecular pathways of only the archetypal hypothalamic regulatory system has failed to yield a full answer to the problems of preventing or treating human obesity.
So what of free will? Regardless of genes or early experiences, there are saints and heroes who can conquer eating behavior by self-imposed starvation for religious or political ends. Lesser souls may respond to injunctions for brief fasts or diets, but for the great majority of us, exercising our will is no long-term answer to the worsening problem of obesity. What should be our perspective on this persistent, trying, often embarrassing problem?
First, keep in mind that eating is one element in a complex set of behavioral and metabolic changes that create and sustain obesity. The roots of the problem seem more and more likely to be found in gene-environment interactions in early development. As adults, complex functions of our brain are at the interface between our environment of abundance and the set-point for fat storage that is a legacy of our patterns of food intake in early life. Our challenge in combating obesity is not to manipulate one or another element in the adult diet, nor to rely on new drugs to alter some element of the biochemical controls of fat storage. Most certainly it is not to make dieting a cultural obsession and an incessant individual preoccupation. Rather our challenge is to use information from nutritional science and molecular genetics to learn how and when the interaction of nature-nurture creates obesity. As the many clues harvested from the molecular-genetic revolution come together to illuminate that complex interaction, we may reasonably hope, one day, to understand how to intervene successfully in early life to maintain all the good of environmental opportunity without the penalty of lifelong obesity.
- Grady, D. “Hormone that causes full feeling is found.” The New York Times, August 8, 2002.
- Feldman, D. “What happened to human will?” The Wall Street Journal, Letters to the Editor, August 13 2002, A21.
- Newburgh, LH, and Johnston, MW. The nature of obesity. Journal of Clinical Investigation 1930; 212:197-213.
- Hirsch, J. “Hypothalamic control of appetite.” Hospital Practice 1984; Feb.:131-138.
- Grinker, J, Hirsch, J, and Smith, DV. “Taste sensitivity and susceptibility to external influence in obese and normal weight subjects.” Journal of Perspectives in Social Psychology 1972; 22:320-325.
- Glucksman, ML, and Hirsch, J. “The response of obese patients to weight reduction: I. A clinical evaluation of behavior.” Psychosomatic Medicine 1968; 30:1-11.
- Glucksman, ML, Hirsch, J, McCully, RS, Barron, BA, and Knittle, JL. “The response of obese patients to weight reduction: II. A quantitative evaluation of behavior.” Psychosomatic Medicine 1968; 30:359-373.
- Grinker, JA, Glucksman, ML, Hirsch, J, and Viseltear, G. “Time perception as a function of weight reduction: A differentiation based on age at onset of obesity.” Psychosomatic Medicine 1973; 35:104-111.
- Glucksman, ML, and Hirsch, J. “The response of obese patients to weight reduction III. The perception of body size.” Psychosomatic Medicine 1969; 31:1-7.
- Leibel, RL, Rosenbaum, M, and Hirsch, J. “Changes in energy expenditure resulting from altered body weight in man.” New England Journal of Medicine 1995; 332:621-627.
- Knittle, J and Hirsch, J. “Effect of early nutrition on the development of rat epididymal fat pads: Cellularity and metabolism.” Journal of Clinical Investigation 1968; 47:2091-2098.
- Johnson, PR, Stern, JS, Greenwood, MRC, Zucker, LM, and Hirsch, J. “Effect of early nutrition on adipose cellularity and pancreatic insulin release in the Zucker rat.” Journal of Nutrition 1973; 103:738-743.