Rudy Leibel’s genes may have predisposed him to become a brilliant scientist, but his decision to spend his life trying to discover the cause of obesity was not predestined. That choice was influenced by an angry mother. Not Leibel’s mother, but the mother of a fat boy named Randall. They met in 1977. Rudolph L. Leibel was a rising star on the Harvard Medical School faculty, an assistant professor of pediatrics at Cambridge City Hospital, in Massachusetts. A busy public hospital in a working-class neighborhood, Cambridge City received its share of tough pediatric cases: children with meningitis, toddlers with bones broken by abusive parents, teenagers who had attempted suicide. Leibel, a scholarly young doctor who favored neat bow ties and fashionably long hair, was revered by the hospital’s pediatric residents for his ingenious rescues of seemingly hopeless cases.

The residents liked to recount the story of one young patient who had tried to kill himself by taking an overdose of chloroquine, a drug

prescribed to travelers to prevent malaria. Leibel consulted a toxicology textbook and found the prognosis grim: doses in the range that the boy had swallowed were uniformly fatal because the drug impaired the functioning of the heart’s natural pacemaker. Within hours of such an overdose, the victim invariably died from cardiac arrest. Leibel persuaded the director of the adult cardiac care unit to admit the child, who at that point still seemed fine, and to hook him up to an electronic heart monitor. He arranged to have a cardiologist stand by, and then he waited at the bedside. When the boy’s heart suddenly stopped several hours later, Leibel and a medical team promptly administered CPR, threaded a pacemaker into the patient’s heart, and started it up again. The case became a hospital legend.

But in the spring of 1977 Rudy Leibel encountered a child he couldn’t rescue. Randall was a severely overweight boy whose mother had brought him to be examined by the young professor, who specialized in hormone disorders. Leibel could find no evidence of a hormone deficiency or of any other known medical cause of Randall’s obesity; the boy was simply fat. When he told Randall’s mother there was little he or anyone could do for her son, she erupted.

“Let’s get out of here, Randall,” she snapped, heading for the door. “This doctor doesn’t know shit.”

A quarter of a century later, doctors know quite a bit more about obesity—thanks in part to the gauntlet thrown down by Randall’s mother. Chastened by her words, Leibel soon traded his post as a Harvard professor for the low-paying toil of a rookie laboratory scientist, moving his family to New York and taking a job in the Rockefeller University laboratory of Jules Hirsch, an eminent obesity researcher. He and Hirsch performed extensive studies, expanding on work by other scientists, that detailed how the body responds either to weight gain or to weight loss by fighting to restore the status quo. In one of these studies, volunteers were induced to overeat until they gained weight. This proved a remarkably difficult task for Leibel’s research subjects, fat or lean, because their bodies responded by turning up their metabolic rates, boosting the levels of certain hormones, reducing hunger, and burning up more calories as heat—all in an unconscious but coordinated effort to get back to the original weight. If people’s intake

was restricted so that they lost weight, their bodies fought back even more fiercely. Their metabolism slowed, they moved around less, their muscles burned fewer calories when they exercised, and they felt constantly and uncomfortably hungry. A host of physiological defense mechanisms swung into play, aimed at regaining the lost pounds.

Findings like these persuaded Leibel that such tight physiological regulation of body weight must mean that the brain was receiving a chemical signal from the body’s fat stores. That conviction ultimately led to the discovery of leptin, a hormone produced by fat cells that became the key to a new biological understanding of how appetite and weight are controlled. Animal studies proved that leptin was the long-sought molecular message that traveled through the circulatory system from fat cells to the brain, signaling that energy stores were sufficient and that it was safe to stop eating. Mice that were genetically incapable of producing leptin ate nonstop and grew enormously tubby. Treating such mice with leptin normalized their body weight.

When the gene for leptin was identified and sequenced in 1994 as a result of an intensive collaborative effort between Leibel and Jeffrey M. Friedman of Rockefeller University, many people (and some drug companies) predicted that the newly identified hormone would become a miracle cure for obesity. They assumed that fat people must be lacking in leptin and that dosing them with it would make them lose weight. It has not turned out that way. Most obese people make plenty of their own leptin, but for unknown reasons their brains are relatively resistant to the hormone’s effects, so that even large doses don’t work very well as a weight-loss drug. Recent findings by Leibel and others suggest, however, that leptin may have a future role as a treatment that helps people keep weight off after they’ve lost large amounts. A fall in leptin levels occurs with loss of body fat and seems to trigger the physiological changes that make people regain lost pounds, so boosting leptin levels after weight loss may help prevent that gain.

The discovery of leptin transformed the science of obesity by persuading the research community that obesity had a biological basis. Almost overnight, hundreds of talented scientists the world over became eager to investigate how appetite and weight are regulated. Scores of papers on the subject are now published each year, and every few

months another small but important piece of the immensely complicated genetic and biological puzzle falls into place; another hormone or cellular receptor is pinpointed as a possible target for future new treatments.

Leibel—his hair now gray and cropped short, his bowtie and button-down shirt replaced by a soft crewneck sweater—heads a laboratory that occupies two floors of a gleaming new research building in upper Manhattan, filled with gene-sequencing equipment and cages of mice and staffed by industrious young scientists. As director of molecular genetics at Columbia University, he and his group are working to identify the major genes that make so many people dangerously prone to obesity and to one of its frequent consequences, diabetes.

What would he say to Randall’s mother now? To begin with, if she walked into his office today, he’d be able to assure her that Randall’s problem was in large measure biological, and not simply the result of faulty parenting or lack of willpower. “There really is a biology to the regulation of body weight, just as there is a biology to the regulation of height or blood pressure or eye color,” Leibel says. “I would say to her, ‘Randall has a disorder of a regulatory system that is important for the control of weight.’”

The years since the discovery of leptin have been hailed as a golden age for obesity research. In little more than a decade, scientists have sketched the broad outlines of the biological system that regulates body weight and have begun filling in the details. The control centers for tracking energy balance and regulating body weight are located primarily in the hypothalamus, a small part of the brain that specializes in integrating messages from many parts of the body and orchestrating the organism’s response to its environment. The hypothalamus communicates by nerve pathways and chemical signals with many other brain areas, as well as with the organs that make up the cardiovascular system, the digestive system, the reproductive system, and the endocrine system (the glands that produce circulating hormones). It uses its output both to modify conscious, purposeful behavior such as food-seeking and to fine-tune unconscious processes such as metabolism,

reproductive cycles and the level of arousal, and spontaneous physical activity. Leibel points out that unconscious signals sent by the hypothalamus to the cerebral cortex, the “thinking” part of the brain, thus contribute to such conscious actions as ordering a pizza or having a second piece of pie. “Just because a behavior is involved does not mean that all aspects of the behavior are ‘voluntary’ in the usual sense of the word,” he says.

Because taking in food and maintaining sufficient energy stores are necessary for survival and reproduction, our bodies are designed to preserve these functions at all costs. The system for maintaining body weight is like a castle surrounded by multiple walls, a computer operating system with many built-in backups, or the redundant controls of a commercial airliner. It evolved to fight starvation, so it is engineered according to the principle that storing too much energy is preferable to storing too little. During most of the several million years of human evolution, a tendency to store extra body fat during times of plenty has bestowed a marked survival advantage. As Leibel observes, if we still lived in the environment of 100,000 years ago, “Randall would be king.”

What are the brain’s strategies for keeping body weight constant? In issuing its instructions, the hypothalamus can respond to information from the environment in three general ways. It can influence food intake by increasing or decreasing appetite. It can fine-tune the body’s metabolic rate—the rate at which it burns calories merely to stay alive—by sending messages to the autonomic nervous system and to endocrine glands such as the thyroid, the insulin-producing cells in the pancreas, and the adrenals, which regulate metabolism. And it can further affect the body’s total expenditure of calories by adjusting how much energy is released as heat during certain cellular processes or through muscle activity such as exercise or fidgeting.

The main appetite control center of the hypothalamus is located in an area called the arcuate nucleus. Within it are populations of two different types of nerve cells. One type of cell makes a pair of chemicals—neuropeptide Y or NPY, and agouti-related protein, or AGRP—that transmit signals to other nerve cells to increase appetite. The other type makes a pair of substances—POMC and CART—that relay signals with the opposite effect, decreasing appetite. (The unwieldy names

of some of the chemical messengers in this system make it seem more mystifying than it is. POMC stands for proopiomelanocortin; CART stands for cocaine-and-amphetamine-regulated transcript.) These two types of nerve cells communicate with each other, and both types also send opposing messages to a third group of nerve cells that contain a signal-receiving protein on their surfaces called the melanocortin 4 receptor (MC4R). Depending on whether the activity of the NPY/AGRP cells or the POMC/CART cells predominates at a certain time, the net effect is to turn appetite up or down.

The NPY/AGRP cells and POMC/CART cells in the arcuate nucleus do not send their signals at random; they respond to messages coming in via the circulation or nervous system from other parts of the body. These messages convey both long-term information about the status of body energy stores and short-term information, such as the current circulating level of glucose and the presence or absence of food in the intestinal tract. The role of nerve cells in the arcuate nucleus and in related areas of the hypothalamus is to integrate minute-to-minute information on the body’s nutritional status and to respond by adjusting food intake and energy use in order to keep body weight constant—in other words, to keep the body in “energy balance.”

Where do the messages being sent to the brain originate? Leptin and to a lesser extent insulin carry information about long-term energy depots. Leptin is an emissary from fat tissue, and its level in the circulation reflects how much fat is stored in the body. Leptin’s chief function seems to be to protect energy stores and prevent starvation. It also serves as a link between nutritional status and the reproductive system, probably helping to prevent pregnancy if energy stores are inadequate. (Puberty does not occur normally in girls whose bodies do not make leptin, and from puberty onward, women’s leptin levels are two to three times higher than men’s.)

When an animal’s or a person’s food intake is severely restricted, leptin levels drop within 24 hours—well before fat stores have been significantly depleted by being burned for energy. The fall in leptin triggers an immediate lowering of the metabolic rate, increased hunger, and a rise in food intake, as well as some suppression of the reproductive and immune systems. These responses seem designed to ward

off the threat of starvation by protecting energy stores and cutting back on noncritical energy expenditure. As I mentioned earlier, the body’s response to high leptin levels, such as those found in overweight children or adults, is far less dramatic.

Insulin, the hormone produced by the beta cells of the pancreas, is released into the bloodstream in response to glucose from food. It helps direct the body’s use and storage of this key fuel, as well as the balance between the storage and burning of fat. Insulin levels fall during fasting and rise in obesity. Some nerve cells in the brain sense and respond to insulin as another signal of overall nutritional status. Some brain cells also respond directly to circulating levels of fuels such as glucose and free fatty acids.

The brain also receives messages from the digestive tract. Constant updates about food availability and the timing of meals are relayed to the hypothalamus by various messenger molecules released by cells in the stomach and intestinal tract. Ghrelin is a recently discovered stomach hormone that signals to the hypothalamus when it is time to eat; it may also help determine the level of hunger. PYY, another signaling molecule, is produced in certain portions of the intestines in response to the arrival of food and apparently informs the brain when it is time to stop eating. A number of other digestive tract hormones are also released in response to nutrients. Some of these signals from the gut may turn out to play important roles in appetite, feeding, and energy balance.

The idea of two opposing groups of nerve cells issuing signals to turn appetite up or down is a simple and elegant concept, but it is nevertheless an incomplete picture of how the brain regulates body weight. Scientists have identified a number of additional chemical transmitters and nerve pathways within the brain that also influence appetite and energy expenditure. For example, nerve cells in an area of the lateral hypothalamus make a substance called melanin concentrating hormone, or MCH, that seems to play a role in the drive to feed. Mice with too much MCH are obese, and mice unable to make MCH are lean, eat little, and burn lots of calories. The nerve cells that produce MCH receive messages from both the appetite-inducing (NPY/ AGRP) cells and the appetite-suppressing (POMC/CART) cells of the

arcuate nucleus. Various other signaling chemicals widely present in the brain (and, in some cases, elsewhere in the body) also affect hunger, satiety, metabolic rate, and fat storage, including a family of appetite-boosting brain chemicals called endocannabinoids, related to the active ingredients in marijuana.

Our bodies’ elaborate mechanisms for regulating appetite and food intake evolved to ensure survival, but we also eat because food is enjoyable. The pleasure associated with eating may serve as an additional survival mechanism, yet it can also drive humans (and animals) to eat more calories than they need, especially when the food before them looks, smells, and tastes delicious. Human eating behavior is highly influenced too by external cues and routines, by social situations, and by other factors such as mood and stress. Sensory input from smell and taste receptors in the nose and mouth sends signals to many areas of the brain, a fact that helps explain why a specific smell or taste can evoke a flood of feelings, memories, and associations. Imaging studies have shown that when people are presented with appetizing, good-smelling food, many regions of the brain become metabolically active and “light up” on scans.

Scientists know less about the brain pathways and signals that produce the rewarding or comforting sensations of eating than they do about the ones that regulate appetite. A brain area called the nucleus accumbens, implicated as a “reward center” active in drug addiction, is thought to be involved in the pleasure associated with food, although additional brain regions probably also participate. The nucleus accumbens receives input from the cerebral cortex (the “conscious” brain) about sensory and social factors in the environment that influence eating as well as from the areas of the hypothalamus that regulate appetite and feeding. Opioid receptors—the cell-surface proteins that respond to narcotics such as heroin—are thought to be involved in producing the pleasant sensations associated with food. The ubiquitous transmitter chemicals dopamine and serotonin, which relay messages along nerve pathways in many regions of the brain, are also believed to affect feeding behavior and the rewarding aspects of food. The fact that nerve pathways and brain cells associated with pleasure are activated by both food and drugs does not mean that food intake

should be considered an “addictive” behavior. As Leibel points out, substances that commonly produce addiction, such as heroin, tobacco, and alcohol, are not critical to survival, but all animals must eat to live.

Hormones arriving from elsewhere in the body can influence the brain’s perceptions of food and can even contribute to conscious cravings for certain kinds of foods. For instance, high levels of leptin blunt the perception of sweet tastes. A recent study found that in rats steroid hormones such as corticosterone, released by the adrenal glands in response to chronic stress, stimulated the animals to eat sweet or high-fat food, which calmed them. (Humans whose adrenal glands make too high a level of steroid hormones, or those who take steroids as drugs, also tend to have an increased appetite and may eat more food than they need.) Findings like these may help explain why people who are depressed or anxious often seek out specific “comfort foods.”

The result of this complicated dance of signals between the brain and the rest of the body is that human beings, whether lean or obese, eat tens of millions of calories over the course of their lifetimes, burn up most of that energy to stay alive and move around, and tend to keep their body weight remarkably constant at a personal “set point.” They store any calories that they do not use up, mostly in the form of fat tissue. However, fat tissue is not just a passive storage depot, like a jar of olive oil sitting in the cupboard. In addition to fat cells, fat tissue contains nerve cells, immune system cells, and other components. As mentioned earlier, fat cells themselves are active performers in the dance of signals, processing fuels and sending out messages, in the form of hormones and other substances, that influence the workings of the brain and other organs and tissues.

Although leptin is the best-known hormone produced by fat cells, there are at least eight or nine others, and the list keeps growing. They include resistin, which interferes with the body’s handling of glucose; adiponectin, which promotes glucose utilization and fatty acid oxidation; and various other proteins that influence the immune system, kidney function, and blood clotting. In addition, fat cells actively metabolize steroid hormones such as male and female sex hormones from the reproductive system and glucocorticoids (cortisol and related chemicals) from the adrenal glands. Metabolism and release of steroid

hormones by fat cells stored inside the abdominal cavity (visceral fat) is thought by scientists to play a central role in producing the metabolic syndrome—the pattern of abnormalities, described in Chapter 1, that is increasingly occurring in overweight children and that can lead to diabetes, heart disease, and other chronic illnesses.

If Randall were to become Leibel’s patient today, he might undergo testing for a genetic cause of his obesity. A few unlucky people are born with a single genetic mutation that stacks the deck so overwhelmingly that they become severely overweight almost no matter what their environment is. At least five different “obesity genes” have been identified that are so critical to the regulation of appetite and food intake that certain mutations in any one of them can produce extreme obesity. These rare mutations cause “monogenic” or single-gene obesity.

In 1997, three years after the report of the discovery and sequencing of the gene for leptin in mice, a team of British researchers led by Stephen O’Rahilly reported the cases of two children, cousins in a large Pakistani family living in England, who had suffered from severe obesity since infancy. Their brothers and sisters were not overweight. The girl, at the age of 9, weighed 200 pounds and had already undergone an orthopedic operation because her fatness had bowed her leg bones. Her cousin, a boy, weighed 64 pounds as a 2-year-old. Both children had been normal-sized infants at birth but had insatiable appetites. They were not diabetic, and their bodies burned calories at normal rates. Their obesity was chiefly the result of constant eating: their bodies were more than 50 percent fat.

Tests showed that both children had a mutation in the gene for leptin. Their fat cells could not make the hormone, so their brains were not receiving a critical signal needed to regulate their appetites. The pair of cases represented the first discovery of a single-gene cause of obesity in humans. When doctors began giving the cousins regular leptin injections, their food intake fell dramatically and the fat virtually melted off their bodies. Several years later the weights of both children are normal for their ages. The older cousin, now a teenager, progressed normally through puberty like her schoolmates with the help of her leptin treatments.

Without leptin these children—and a few others who have been found to carry the same kind of rare mutation—are unable to transmit messages from their fat cells to their brains about how much energy the body has stored. As a result, they eat voraciously and become obese. So do a few equally rare individuals whose brains cannot sense the presence of leptin because of a mutation in the gene for the leptin receptor, a key docking site for the hormone. A third gene contains the instructions for making an enzyme called prohormone convertase 1 (PC-1), needed for the production of both leptin and insulin, yet another hormone that’s an important player in weight regulation. Children with mutations in any of these three genes—the gene for leptin, for the leptin receptor, or for PC-1—are severely obese. Because of leptin’s effects on the reproductive system, they also fail to show signs of puberty upon reaching early adolescence, a fact that often leads to the diagnosis of their genetic condition.

A fourth “obesity gene” contains the code for proopiomelanocortin or POMC, a previously mentioned appetite-suppressing chemical made by the hypothalamus. POMC helps regulate not only appetite but the functioning of the adrenal glands (important for salt and fluid balance, metabolism, and stress responses) as well as the body’s manufacture of pigments that color the skin and hair. When the gene is mutated, the messenger fails to perform any of its functions, and so children with POMC mutations are overweight and red-haired and have adrenal glands that don’t work properly.

Mutations in a fifth gene are by far the most frequent single-gene cause of obesity yet discovered, accounting for up to 5 percent of cases of severe childhood obesity. (Testing so far has been performed mainly in children of European ancestry; such mutations may turn out to be less common in obese children from other ethnic groups.) The affected gene contains instructions for making the cell-surface protein called the melanocortin 4 receptor (MC4R). These receptors, also mentioned earlier, are found on certain nerve cells in the hypothalamus, where they serve as docking sites for signaling chemicals involved in appetite regulation, especially the appetite-suppressing signal derived from POMC. If the cells of the hypothalamus lack functioning MC4R receptors because of a genetic mutation, they cannot sense the signal’s presence and appetite is not suppressed. People with this kind of mutation

are abnormally hungry: they overeat and become obese. Children with MC4R receptor mutations, besides being heavy, are tall for their age and have unusually dense bones.

In most cases, identifying one of these gene mutations as the cause of an individual’s obesity does not mean that a doctor can successfully treat or cure it. Nevertheless, understanding these monogenic causes of very severe obesity has given scientists a precise explanation for what causes the weight problem in people with such mutations and has allowed them to fit together pieces of the puzzle showing how the body regulates food intake and fat stores in individuals without such mutations. Finding additional single-gene causes of obesity is likely to lead eventually to the development of far more effective medical diagnosis and treatments. Mutations in single genes “surely do not represent the majority of instances of human obesity—even severe obesity—from what we can tell now,” Leibel says. “But they reinforce this idea that there are single genes that very, very potently and profoundly affect energy balance and body weight in humans.”

Most overweight children don’t need genetic testing as part of their routine medical care, but those who are severely obese may, especially if obesity has developed at a very young age. Hormone problems and genetic disorders cause far fewer than 10 percent of all cases of childhood obesity. Doctors can measure blood levels of certain hormones—such as leptin or proinsulin—as initial tests that might suggest the presence of some mutations. Obesity is also a feature of certain rare inherited syndromes—constellations of abnormalities caused by single or multiple genes. For example, children with Bardet-Biedl syndrome are very overweight and also frequently have extra fingers or toes, degeneration of the retinas of their eyes, and developmental delays. Children with Prader-Willi syndrome are often scrawny or underweight for the first year or two of their lives, then develop an insatiable appetite and become severely obese; they are also unusually short, have poor muscle tone, and suffer from mental retardation or learning disabilities.

Because Leibel specializes in the genetics of obesity, he regularly receives calls and e-mail messages from doctors around the country who are faced with a seriously overweight youngster and want to know

whether they are dealing with one of the known mutations or with some other inherited cause of the condition. If a case seems to fit the profile of one of the genetic forms of obesity, he asks the doctor to send a blood sample for testing. On a day when I visited, he had just received a message about a 340-pound 9-year-old. “The odds that there’s something amiss there are extremely high,” he said. “We will look at that child very, very carefully for variants in these genes and others … without necessarily anticipating that we’ll be of any help to that child in the immediate sense.”

Obese people today are living in a time that is both promising and painfully difficult. Although doctors have begun to recognize that body size is to a great degree determined by a person’s genetic and biological vulnerability to weight gain and thus largely beyond an individual’s conscious control, the science of obesity is still young. Despite the rapid pace of new discoveries in the field—and the wealth of scientific talent and pharmaceutical and government funding now focused on it—specific, highly effective treatments for obesity have yet to be discovered.

Meanwhile, we are facing an expanding public health crisis that clearly has not arisen because of newly mutated genes. Obesity is increasing at an unprecedented rate in the United States and in many other countries, and recent shifts in the environment are undoubtedly at the root of the epidemic. A “toxic environment,” in the words of researcher Kelly Brownell of Yale University, is playing on individual genetic vulnerability to produce unhealthy weight gain in more and more people. And if environmental factors are at fault, then by changing the environment—or by learning ways in which we can consciously change our responses to it—it may be possible to slow down or even reverse the trend.

At a time when overweight people might be expected to take a measure of comfort in the recognition that their problem has a biological basis, society is delivering a confusing double message. Half of the message says: obesity is a disease, much like high blood pressure, and treatment should be covered by insurance. The solution, when it is discovered, will be a medical one. The other half says: for many people,

unhealthy weight gain can probably be prevented if we can figure out which environmental factors contribute to it. Be more active, drink less soda, change your diet, and you can somehow escape it or ameliorate it.

How can this apparent contradiction be understood? And how can we, individually and as a society, work on preventing obesity—especially in our children—without continuing to make fat people feel, as they have for generations, that their weight problem must be all their fault? To answer the question we must explore scientists’ current understanding of why so many children and adults are becoming overweight. Their genes may have established their individual risk of storing excess body fat, but factors in the environment are what make it happen.

The genes children inherit from their parents appear to be the strongest influence on whether they will become overweight, either in childhood or as adults. Some of the best scientific evidence supporting the hefty contribution of heredity comes from studies of identical twins and from studies of children who were adopted—the kind of research that has classically been used to tease apart the tangled influences of genes and environment on a host of conditions ranging from high blood pressure and colon cancer to various mental illnesses. In the case of obesity, although many studies suggest that genes are a bigger player than environmental factors, the modern environment may be shifting that balance somewhat.

For example, in 1990 psychiatrist Albert J. Stunkard of the University of Pennsylvania reported on 93 pairs of identical twins who had been raised in separate families and 154 pairs who had grown up together. The weight, height, and body shape of the identical twins separated at birth were astonishingly similar—almost as much alike as the weight, height, and bodies of twins who had grown up in the same family. Stunkard concluded that hereditary factors account for about 70 percent of obesity and environmental factors for only about 30 percent. Moreover, the study suggested that any impact of environment on obesity appeared to be derived from factors common to society at large, not from factors operating within the family.

In another study published in 1986, Stunkard and colleagues

looked at genetics versus family environment in a group of 540 Danish people who had been adopted as infants. Adult adoptees were categorized by “weight class”: thin, medium, overweight, or obese. The weight class of the adult adoptees correlated with the BMIs of their biological parents (especially those of their mothers) and did not correlate at all with the BMIs of their adoptive mothers or fathers. Overweight adoptees tended to have overweight biological parents; lean ones tended to have lean parents. “Genetic influences have an important role in determining human fatness in adults,” the research team concluded, “whereas the family environment alone has no apparent effect.”

No apparent effect! The tone of these studies on twins and adoptees makes it seem as if it doesn’t matter how parents feed their babies, what kind of snacks they provide, or whether they encourage their children to turn off the television and play outside. No matter what parents do, a child’s weight and body shape will probably resemble the mother’s or father’s. “Adoption studies are the strongest evidence of there not being much influence of the family environment” on body size, says researcher Jane Wardle of the Health Behavior Unit at London’s University College. Adopted children “remain as similar to their biological parents as [children who] were raised with their biological parents.”

But not so fast. Not all studies have concluded that heredity predominates over environmental factors in determining who becomes overweight. In a recent review of about 50 studies of twins, adoptees, and nuclear families, researchers concluded that genes account for only about 25 to 40 percent of the variation in people’s tendency to store excess body fat. Some researchers suggest that people can probably be categorized according to their degree of inherited risk: genetic obesity, strong genetic predisposition, slight genetic predisposition, and genetic resistance to becoming overweight.

One reason why studies have yielded such widely varying estimates of the role of heredity in obesity is that such estimates depend in part on the environment of the people being studied. If their environment is one that promotes weight gain, the role of genetic factors will appear smaller than if the environment is less obesigenic. Obesity is not unique

in this respect. Many human characteristics—as well as many diseases—are the product of varying degrees of interaction between “nature” and “nurture.” It’s helpful to compare the evidence for heredity’s role in obesity with the evidence for its role in some other conditions. For example, research indicates that the influence of genetics on body weight is as strong as its influence on height. Studies of twins tell us that genetics plays as great a role in establishing obesity risk as in the risk of developing schizophrenia, alcoholism, or high blood pressure.

But while it’s true that a child’s genetic endowment determines his or her vulnerability to weight gain, genes alone don’t dictate what each individual’s weight will be. If genes accounted for everything, the current epidemic of obesity would not be happening. Many aspects of our modern environment are undoubtedly contributing to that epidemic by encouraging people to eat more and to move around less. Environmental factors operating before birth and during infancy may also be influencing children’s brain development and thus the ability of their bodies to regulate food intake. Parents—as well as other concerned adults—can affect how children handle their environment to some extent, by teaching good eating habits and by helping them be as active as possible. Nevertheless, researchers studying the epidemic believe that a comprehensive solution to the rise in obesity will require broad environmental and social changes.

Most of the modern world’s impact on body size comes from our common, shared environment typified by the abundance of cheap, tasty, high-calorie foods; our reliance on cars, elevators, and other forms of motorized transportation; our sedentary lifestyle; and the difficulty of incorporating walking and other kinds of activity into our daily routines. To halt the obesity epidemic, we will have to identify which of these factors are most strongly contributing to weight gain and find ways to alter them—a daunting task.

The vast majority of children and adults who are overweight do not have a single defective gene as the cause of their weight problem. Instead, each has multiple genes that predispose that individual to eat a few extra calories, burn up less energy than they take in, or store the

excess as fat. Like the members of a band, this collection of genes plays together to determine their possessor’s vulnerability to putting on extra pounds. One person’s band is not the same as another’s: they may have some instruments in common and others they do not share. But each individual’s combo of obesity-related genes plays along with various factors in the environment to determine that person’s chances of becoming overweight.

How many genes might be at play? Researchers don’t yet know. At one time many thought there must be a single obesity gene—and when leptin was discovered, some believed at first that the master gene had been found. Now at least 60 genes are being investigated, and some scientists fear as many as 100 genes could be contributing to obesity risk. “One hundred genes, each with 1 percent effect,” says Rudy Leibel. “Which from a genetic point of view is a nightmare.”

Leibel’s own suspicion, after examining patterns of obesity inheritance in families drawn from various populations and ethnic groups, is that the number of important players is much smaller. He suggests that each person may have up to a dozen genes that combine to determine individual obesity risk. Some of them—perhaps six or seven—are probably major players that help determine the likelihood of obesity in people all over the planet. The rest may be due to gene variants more common in one ethnic population than another, so that genes predisposing someone of Mexican descent to obesity might differ from those determining risk for Polynesians. “This is what makes the genetics so complicated,” Leibel says. “We don’t know which ones are the major players and we don’t know which ones are the minor players. So we don’t know how to apportion our efforts.”

Although genes determine individual vulnerability to weight gain, environmental factors help dictate the outcome—the weight that a person reaches during childhood or adulthood. “What the genetics does is, it tells you, if you have 100 people, how they’ll line up relative to each other in most environments,” Leibel says. “It tells you, ‘This is number 1 and this is number 100,’ and how to rank people in between, in terms of body fat. What it doesn’t tell you is what those 100 people are going to look like specifically in any given environment.” For example, if 100 people were exposed to famine and had to subsist on a

starvation diet, they would all become thin—but some would lose less weight than others. “Some of them are going to weigh 40 pounds and some of them are going to weigh 70, and this is going to be due to the genetics of how they dispose of the calories in the presence of severe calorie restriction,” notes Leibel. “And the same is going to be true if you put them in fast food heaven. They’re all going to get fatter, but they’ll probably all get fatter in the same rank order.”

Evidence of how tightly the body regulates its own energy balance is the fact that the majority of people do not become severely obese even in today’s calorie-rich environment. The average person consumes 7.5 million to 10 million calories in the course of a decade, yet Americans and people in other Western countries typically gain only half a pound to a pound each year during their adult lives. In order to gain any weight at all, they must eat more calories than they burn—but the amount needed to account for this degree of weight gain is only about 10 to 20 calories per day, or about the equivalent of one Ritz cracker. That’s less than 1 percent of an adult’s average daily intake.

A calorie imbalance this small can’t be reliably measured by researchers studying people in their normal habitat. To perform quantitative studies on how weight gain and loss affect people’s appetite and metabolism, Leibel and his associates had to confine his volunteers in hospital research wards and measure every mouthful. He found, surprisingly, that obese people do not eat more than lean people in proportion to their body size. Of course, an obese person does have to consume a larger number of calories per day than a lean person of the same height simply to support a bigger body mass. But when allowances are made for the differences in body size, the number of calories consumed “per pound” is the same. Nor do obese individuals have slower metabolisms than lean ones, as long as they remain at the weight that is “normal” for them. They still balance their calorie intake and output very precisely to maintain a constant weight, just as lean people do. But the weight that they maintain is higher. Obesity “is a disorder which is the result of very, very small differences” in physiology, Leibel says. “You don’t need a big error [in energy balance] to get a very big aggregate change in body mass over time.”

The laws of thermodynamics dictate that people who are overweight must, at some point, have taken in more energy than they spent in order to gain the extra pounds. “There’s no way around it,” Leibel says. “You cannot eat like a canary and become the size of a pterodactyl.” But in most cases, once obese people have reached a personal set point determined by their own physiology, their weight stabilizes. Their food intake and their metabolic rates, when adjusted for their body size, are similar to those of lean people.

However, when a person loses weight, the situation shifts dramatically. If lean or obese people lose 10 percent to 20 percent of their body weight, their bodies respond by becoming more efficient and using less energy in an effort to conserve calories and replenish the lost fat stores. This reduction in energy expenditure is much larger than would be expected for the amount of weight lost. “You see an adjustment of energy expenditure which is far greater—about 15 percent greater—than you would have predicted based on the change in body size,” Leibel says. “This is big—and it accounts, almost certainly, for some of the tremendous recidivism to obesity that characterizes 90 to 95 percent of otherwise successful weight reduction.” Studies suggest that about 95 percent of people who lose weight by dieting gain it back within five years.

In someone who has lost weight, resting metabolic rate drops. Muscles also become more efficient, so moving around and exercising burn up fewer calories than they did before the weight loss. There are shifts in hormone levels and in the fine-tuning of the nervous system that reduce energy consumption. In addition, even though the body is using fewer calories, people who have lost significant amounts of weight become uncomfortably hungry. Whether the amount lost was 10 percent of body weight, 20 percent, or even more doesn’t seem to matter: the sensation of hunger is about the same, according to Leibel’s studies. “It’s very uncomfortable,” he says. “Your body is essentially responding as if you were in a partly starved metabolic state.” In many people who have lost weight, that sensation of increased hunger seems to persist, sometimes for years. Forced to fight such insistent signals from their own bodies, most people eventually regain the lost weight.

Leibel believes that, for adults, trying to keep weight off in the face

of the body’s determined effort to gain it back may be as difficult as trying to resist thirst or to consciously control blood pressure. Various studies indicate that regular exercise helps people maintain weight loss by burning calories and increasing metabolic rate. Yet exercise also unconsciously triggers increased food intake. That is why elite athletes in training do not spontaneously lose large amounts of weight: without having to think about it, they eat more to make up for what they burn. Many studies have found that by itself exercise doesn’t produce much weight loss, although it definitely makes people fitter and healthier.

There is some evidence to support the theory that as a child goes through puberty, hormones and other biological influences act on the brain to establish what the permanent set point for body weight will be during adult life. Before puberty, the set point may not yet be firmly established, so loss of body fat may not trigger the same vigorous physiological responses in a child that it does in an adult. This biological difference may explain why some clinical studies have found that overweight children who have not yet entered puberty have higher success rates in losing and keeping off weight than adolescents or adults do. Such findings underscore the urgency of treating obese children as early as possible to help them achieve a healthier body weight.

The combination of genes each person inherits probably operates in various ways to determine individual vulnerability to obesity. “There are many people who have been dealt a hand that, in this environment, makes them become overweight,” says Susan Z. Yanovski, a National Institutes of Health (NIH) official who is coordinating research on obesity prevention. Some genes, for example, endow those who carry them with a slower-than-average resting metabolism or a metabolic propensity to store calories as fat. Some genes may confer a taste for high-fat foods or a tendency to eat a larger quantity before feeling full than other people. Some make their possessors especially calm and sedentary, less likely than others to burn energy by fidgeting, moving around, or exercising.

Some of the most intriguing clues about how genes interact with the environment to make people fat come from studies in the Pima

Indians of southwestern Arizona. The Arizona Pimas have one of the highest rates of obesity in the world—rivaled only by the populations of a few western Pacific islands—as well as the highest reported prevalence of type 2 diabetes, a form of the disease that frequently develops in fat adults and is becoming increasingly common in overweight children. Surveyed in 1988 when the current national obesity epidemic was just getting under way, more than 80 percent of Pimas between the ages of 20 and 55 were overweight, and 40 to 70 percent were obese, with BMIs above 30. More than half of Pima adults over the age of 35 have diabetes.

For many years NIH researchers based at a government laboratory in Phoenix have been studying Pima volunteers from the nearby Gila River Indian Community to investigate why the Pimas’ genes predispose them so strongly to weight gain. The Pimas, who call themselves Akimel O’odham (the River People), have lived in southwestern Arizona for at least 2,000 years. They practiced traditional methods of agriculture and farming until white settlers diverted the Gila River in the late nineteenth century. Today they eat a modern American diet, and many live on an arid reservation in the Sonoran Desert where snakes, packs of roving dogs, and extremely high temperatures make outdoor exercise dangerous.

For most of their history, the Pimas’ traditional lifestyle as subsistence farmers in a harsh environment exposed them to periods of extreme privation and placed strenuous demands upon their bodies. Researcher James Neel proposed in the 1960s that such extreme environmental pressure on a human population might have favored the selective survival of individuals who carried a “thrifty gene,” one that enabled them to store calories as fat during periods of plenty so they could live through periods of famine. Although the concept of a single thrifty gene has given way to the current “polygenic,” or many-gene, theory of obesity, most researchers still agree with Neel’s central idea, that a history of privation tends to make a population more vulnerable to weight gain and obesity. According to this theory, the extreme obesity seen in inhabitants of certain Pacific islands may occur because their ancestors frequently had to survive similar privation, perhaps during long inter-island canoe voyages.

In times of famine, “you would expect the fattest individuals to be the survivors,” says Eric Ravussin of Louisiana’s Pennington Biomedical Research Center, who spent 14 years studying the Pimas. “This gene pool has been protective for Pima Indians over their history.” In a 1994 study Ravussin compared a group of Arizona Pimas with a group of Pimas who live in a remote mountainous region of northern Mexico. Although the Mexican Pimas speak the same language as members of the Arizona group, they are the descendants of people who separated from the Arizona Pimas about 1,000 years ago. They are physically active subsistence farmers, with a lifestyle similar to that of the Arizona Pimas’ ancestors. Even though the two groups are thought to be closely genetically related, the Mexican Pimas are generally lean. In a comparison study that matched Mexican and Arizona Pimas by age and sex, Ravussin found that the Mexican Pimas weighed, on average, 57 pounds less than the Arizona Pimas. Their average BMI was 24.9 (within the normal range) versus 33.4 (obese) for the Arizona Pimas studied. Among the Mexican Pimas, the frequency of diabetes was 11 percent for women and 6 percent for men, compared with 37 percent among Arizona Pima women and 54 percent among Arizona Pima men at that time. These findings strongly suggest that it is the modern American diet and lifestyle, interacting with an obesity-prone genetic profile, that have made the Arizona Pimas suffer so severely from weight gain and its medical complications.

Just what is it about the Pimas’ biology that predisposes them to weight gain? For many years, researchers thought the cause might be a slow resting metabolic rate or a tendency to store fat efficiently. But Ravussin and other researchers found that, on average, Pimas’ resting metabolic rate, including that of the slender Mexican Pimas, was not significantly different from that of Caucasians. Certain characteristics did seem to run in families, such as a low metabolic rate or a physiological tendency to burn carbohydrates for energy in preference to fats. Fidgetiness—and the lack of it—also seemed to be inherited tendencies. But the research indicated that such traits explain only a little of the individual variation in obesity risk seen among Pima Indians.

A low rate of calorie burning does not appear to be at the root of the Pimas’ inherited vulnerability to obesity. “Indirectly, through all

this investigating of energy expenditure, we have kind of convinced ourselves that the main culprit must be a tendency to eat in excess of energy requirements,” says Antonio Tataranni, the director of the NIH’s Clinical Research Center in Phoenix. Rudy Leibel notes that studies of animal models of obesity, as well as studies of humans with monogenic obesity, tend to support that hypothesis. The evidence from those studies suggests that the most important contributor to the obesity is intake of excess calories, not a reduction in energy expenditure.

Most of the earlier studies on Pimas were performed with adult volunteers, but recently NIH researchers have begun to focus more attention on children. They have learned, for example, that excess weight gain in Pima youngsters may begin as early as the first month of life. In a 2002 study Robert S. Lindsay and colleagues reported that the pattern of weight gain in Pima children differs markedly from U.S. national norms, with Pima babies putting on significantly more weight for their length between the ages of 1 month and 6 months. Pima children between the ages of 2 and 11 also gain weight faster and have higher BMIs than national norms. Researchers are uncertain whether the rapid weight gain in infancy represents purely fat accumulation, nor do they know whether it’s genetic or whether it’s related to environmental factors during pregnancy or infancy. They are more confident that the rapid weight gain after age 2 reflects a tendency to gain fat. Current and future research will focus in greater detail on family eating habits and Pima children’s food choices, Tataranni says.

Studies in these children, who belong to one of the most obesity-prone populations in the world, serve to underscore the importance of exercise. Pima children between the ages of 5 and 10 are four times more likely to be obese than children in the general U.S. population. Yet even among these children, being active and participating in sports do seem to help protect against both weight gain and the development of insulin resistance, a hormonal condition that is a precursor to diabetes. A 2002 study by Arline D. Salbe and colleagues found that Pima 5- and 10-year-olds who participated in more sports or recreational activities were less likely to be obese. Television had the opposite effect, just as many studies in children from other populations have found. Pima children’s body weight and body fat went up in proportion to the

number of hours of television they watched. Pima children who stayed active between the ages of 5 and 10 were less likely than others to gain large amounts of fat, and their bodies responded more normally to insulin, Tataranni and his researchers found. “Those kids who were able to maintain a more active lifestyle through these five years of observation did a little better,” he says.

Rudy Leibel takes pride in the fact that his genetic research has served to shift blame for fatness away from the people who suffer from it. The ongoing discovery of obesity genes is proof that biological variations in vulnerability to weight gain are the major reason why some people are fat and others are lean. That’s why Leibel views much of the current national debate about measures to prevent obesity with some concern. He points out that no one yet knows precisely what actions will be most effective. “On some level this is a disease that everybody thinks they understand, and yet in fact nobody understands,” he says. “Everybody thinks they’re an expert on this. They can tell you, ‘It’s the Coke in the schools. It’s McDonald’s.’ Everybody has an explanation for it. But nobody really knows—including me and Randall and Randall’s mother.”

Seriously overweight people are doubly cursed: they have a dangerous medical condition that is notoriously resistant to treatment, and the rest of society makes them feel it must be their fault. “Most people who are ‘experts’ on obesity never really understood what it is like to have this problem,” Leibel says. “It is a biological disorder that is attributed by everybody, including the patient, as being due to some failing that you can’t identify…. It’s a heavy burden to bear.”

If everyone in the United States had the same genetic vulnerability to obesity, researchers could conduct a study to determine which environmental factors are most strongly influencing the epidemic. They could easily design trials to compare different strategies for preventing weight gain and learn which ones are most effective. Such a trial, for example, might be theoretically possible in the Pima Indians—who are more genetically homogeneous than the U.S. population as a whole—but it would still have to be a very large and long-lasting study.

Faced with the rapid rise of obesity in the U.S. population—and with the specter of accompanying increases in diabetes, heart disease, and other medical consequences—many researchers and public health officials are not willing to wait for the studies that could answer the question. They are designing and testing prevention programs for children that typically combine several strategies, such as education about healthy eating habits, physical activity sessions, and efforts to reduce television watching. Meanwhile, public and private campaigns are being launched at the local, state, and national levels to change Americans’ diets and encourage them to exercise.

Leibel concedes that a lot of the advice seems like common sense. Some of the changes in behavior being promoted have other well-established benefits. For example, our population will be healthier in many ways if people can be persuaded to walk more, to breastfeed their infants, or to eat more fruits and vegetables. But as a scientist, he cautions that we should not assume either that the obesity epidemic has a single cause or that combating it will necessarily require draconian actions. “A relatively subtle intervention could have a big effect over time,” he says. Yet because scientists can’t measure either food intake or energy expenditure with enough precision in people living normal lives outside a hospital research laboratory, they can’t quantify the relative contributions of excess calories and insufficient physical activity to the obesity epidemic, much less pinpoint the precise roles of many of the “usual suspects,” such as soda and fast food consumption or a reduction in the amount of time children spend playing outside. “We really don’t know what has happened, other than on a very macro, thermodynamic level,” Leibel says. “Food intake is greater than energy expenditure. Period.”

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