Born to be fat

Fifty years ago, an enormously fat mutant mouse emerged in a New England research centre. It marked the start of a long search for a gene that controlled appetite and therefore weight. In 1994, it was finally located. Now the genetic quest is on again - this time for a miracle cure for the obesity pandemic that is rapidly spreading across the world. In the meantime, at least we now know why some people get fat and others don't. Ellen Ruppel Shell investigates

Saturday January 11, 2003
The Guardian

The Hungry Gene by Ellen Shell
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The first time I set eyes on Nancy Wright, she is flat on her back and cruciate. She is vaguely pretty, her eyes frightened but oddly beguiling. Even as she lies splayed and sedated on a trolley in Operating Room 17 at Beth Israel Deaconess Medical Centre in Boston, you can sense that Nancy Wright is possessed of an immutable will.

Nancy once told me that she'd started out life large and kept on going. She didn't mean it as a joke. She weighed 10lbs 4oz when she came into this world, and through childhood ate herself so big that her father thought she had psychological problems. Nancy herself likens her relationship with food to a doomed love affair. "Food has always been my best friend and worst enemy," she told me. Now, in middle age, this dysfunctional relationship has made even simple pleasures difficult. It is getting harder for her to work in her flower garden, harder to play with her five grandchildren. And she keeps getting sick. She has hypertension, high blood cholesterol and sleep apnoea (difficulty breathing). She has tried WeightWatchers and diet pills. They worked, for a while. The pounds melted away, and Nancy thought she'd found salvation. But then, without knowing why, she'd fall off the wagon and her old life would rush back.

People tell Nancy she lacks willpower, but they are wrong. She has plenty. She stayed with the same thankless social services job for 20 years, and with the same thankless husband for 19. As a 50th birthday present to herself, she quit smoking. But food is different. For Nancy, food is more than an addiction, it is like breathing - a constant, throbbing need.

Dr Edward Mun understands all this perfectly. He is a surgeon at Beth Israel Deaconess Medical Centre. What he does is to take perfectly healthy stomachs and replumb them, fashioning them into pouches the size of robins' eggs. On average, patients shed about 60% of their excess weight in about 18 months. Nancy is next in line.

Nancy is 5ft 3ins tall and, at the time of her operation, weighs 19 stone 8lbs. Mun has not promised Nancy success, or even survival. Gastric bypass kills one in 100 patients on the operating table. Mun helps the nurses arrange the layers of sterile drape, leaving exposed a rectangle of stark white skin roughly the area of a shoebox lid. He paints the rectangle orange with antiseptic. The flesh ripples thickly, like a crme brle. With a black ballpoint pen, Mun traces down the centre line from the tip of the breastbone to the navel. A surgical resident traces over that line again and again with a scalpel until the skin bursts open with the force of the fat beneath. There is a smell like hamburgers spitting on a grill. The translucent fat layer glistens yellow under the operating room lights. Mun and the surgical resident exchange looks, then press two palms each on either side of the neatly split skin and ease the fat apart, forming a canyon. There is almost no blood.

Plunging his hand into the cavity, wrist deep, Mun palpates the taut purple liver and gently retracts it to examine the junction between the stomach and the oesophagus. He is now elbow deep, pawing blind for the start of the stomach. Long seconds pass. No one says a word. Suddenly, Mun finds what he's after. "I love this organ," he says, pulling the stomach into glorious view.

Nancy Wright knows that dying on the operating table is a possibility. She knows about the complications - the exhausting anaemia, the painful gallstones and incisional hernias, the infections. But Mun has completed 110 gastric bypass procedures in the past 12 months, and most have gone like clockwork. He reminds me of this as he manipulates Nancy's guts. Taking aim with his Endo-GIA II stapler, which cuts as well as rivets, he divides the stomach into two parts and staples the top portion into a 20-millilitre pouch. An organ that could once proudly contain a litre of Hagen-Dazs can now barely hold a shot glass of yogurt. For a few months at least, Nancy's stomach will no longer have the power to demand a Snickers bar. Mun has tamed it.

Like Nancy, more than nine million American adults are "morbidly obese", roughly seven stone or more overweight. Ten million more are almost there, teetering on the edge. Obesity, the US Surgeon General David Satcher has warned, is quickly eclipsing tobacco as the number one threat to public health. Half the adult populations of England, Brazil, Chile, Paraguay, Finland and Russia are overweight or obese. In China, obesity increased six-fold in the final decade of the 20th century. On some islands in the South Pacific as many as three-quarters of adults are dangerously obese. And adults are not the only victims. In Britain, youth obesity rates have soared by 70% in a single decade.

Americans spend $33bn a year - more than the gross national product of most developing countries - on weight loss products and schemes. We sign lifetime contracts with health clubs, hire personal trainers, buy diet books and low-fat foods by the ton. We spend hundreds of millions on weight-loss medications that can sicken or even kill us, and risk death on the operating table. And, all the while, we grow fatter.

Pudge is not a new thing. Consider the Venus of Willendorf, a hand-sized 25,000-year-old sculpture unearthed early in the 20th century near the Austrian village whose name she bears. She has erupting breasts, a Falstaffian stomach and what appear to be no feet. She is lushly, voluptuously obese. About 100 such statues have been unearthed, and they are thought by archaeologists to be among humankind's earliest artworks. Obesity has its roots in the Stone Age.

Egyptian pharaohs entombed themselves in chambers etched with depictions of their own gorgeous physiques, but studies of their mummified remains betray rolls of belly fat. (Servants were likely the living models for those hard-body renderings.)

Hippocrates, known as the father of western medicine, warned his fellow Greeks that "sudden death is more common in those who are naturally fat than in the lean". The Cretans disdained the obese, and claimed to possess drugs (likely either toxic, purgative, or both) that allowed people to eat as much as they liked without growing fat. Despite their propensity for ritual gorging, the Romans, too, frowned on obesity. Roman women starved themselves, sometimes to death, in an effort to please their demanding husbands and fathers. The Spartans simply exiled their plumper citizens.

Medieval Christian thinkers ranked gluttony as one of the seven deadly sins. In the 18th century, numerous doctoral theses and monologues focused on the problem of obesity. Most famous among these is a discourse on "corpulency" by the Dutch physician, Malcolm Flemyng. He considered obesity a danger and an evil, but he did not dismiss the overweight as lazy or sinful. Rather, he portrayed them as unlucky inheritors of a predisposition that was not entirely within their power to control.

In the industrialised age, mechanisation and mass production made life easier, and portliness was no longer a badge of prosperity. As the working classes grew stout, any vestiges of sympathy for body fat were overwhelmed by an ardent campaign to root it out. Underlying this movement was the new "science" that linked being overweight with ill health.

In the 20th century, newly hatched notions of psychology brought to light the power of the unconscious to shape behaviour. The idea took hold - despite a dearth of hard evidence - that the obese were anxious, unbalanced people who turned to food as a form of sublimation or escape, possibly from sex. Obesity became the subject of serious scientific study.

The Jackson Laboratory in Bar Harbor, Maine, founded in 1929 as a medical research centre, was and is a sort of mouse ranch, squirming with rodents both ordinary and fantastic. There are today 2,500 different strains breeding in 47 "mouse rooms" scattered around the campus. While mice do not in any way resemble humans, they are similar enough genetically to offer a reasonable model for the study of normal and abnormal human biology, as well as of human disease.

In the early 1950s, a mutant suddenly appeared in the lab - a mouse with unusual traits. An animal caretaker first spotted the creature huddled in a corner of its cage, grooming itself. It was furrier than most, but what really stood out was the size of the thing - it was hugely fat. Initially, the researchers diagnosed the mouse as "pregnant". But there were problems with this theory. For one thing, the mouse never delivered a baby. And, on closer inspection, it turned out to be male. The fat mouse ate three times the chow eaten by a normal mouse, pawing for hours at the bar of the food dispenser like an embittered gambler banging away at a recalcitrant slot machine. Between feedings it sat inert. It seemed to have been placed on this earth for no other purpose than to grow fat. The scientists christened the new mouse "obese", later abbreviated to "ob", and pronounced "OB".

At about the same time, a British scientist, Gordon Kennedy, conducted a series of elegant experiments that pointed to something in the fat cells themselves that directly or indirectly controlled feeding in rodents. He concluded from this that body weight in rodents is controlled by a sort of fat thermostat - which he christened a "lipostat" - that senses how much fat there is on the body, and adjusts eating and energy expenditure accordingly to maintain a steady state or "set-point".

Douglas Coleman, a biochemist at the Jackson laboratories, noting these findings and carrying out experiments of his own from the early 1960s, came to believe that eating behaviour in rodents was controlled by a factor in their blood - and that, in turn, might be controlled by one or more genes. When Coleman published his findings in the early 1970s, the prevailing scientific view claimed obesity as a problem of behaviour, not biology. He stuck staunchly to his theory, and continued to search for the mysterious satiety factor for the rest of his career.

Three years after his retirement in 1991 it was found, by a very different sort of scientist.

In July 1980, Jeffrey Friedman - now head of the Laboratory of Molecular Genetics at Rockefeller University - arrived at Rockefeller to pursue a research fellowship. He was assigned to look into the molecular biology of liver regeneration, but it soon became clear that his real interest was to clone the elusive ob gene. Friedman, through a colleague, met Rudy Leibel, a scientist and physician who came to Rockefeller in 1979 and had been searching for Coleman's satiety factor and the ob gene for several years. Like Coleman, Leibel thought that something in the fat cell itself was producing a satiety signal. But what that something was he had not a clue. Leibel had worked with obese and diabetic patients - in particular, children. He had also worked on obese mice in the laboratory, and had seen how they differed fundamentally from ordinary mice. He began to wonder whether there was something amiss in the physiology of obese humans, too - perhaps something, such as iron deficiency, that could be remedied.

He was uncomfortably aware that neither he, nor probably anyone else, knew how to treat obesity. It was while under this cloud of self-doubt that he happened upon a lecture by Ethan Allen Sims, a physician at the University of Vermont College of Medicine who was then exploring the link between obesity and diabetes. Sims was interested in whether the metabolic differences observed between fat and thin people were the result or the cause of their body type. Put simply, he wanted to know whether people are born fat or made fat. He decided that the best way to sort this out was to convince a group of slim volunteers to eat themselves fat and to observe what happened to them when they reduced to their original weight.

Sims was fortunate to have nearby a ready source of experimental subjects: the inmates at Vermont state prison, sufficient numbers of whom were willing to gorge themselves for science. At first the prisoners proved enthusiastic trenchermen, as much as doubling their usual daily intake of food. But as they fattened, they became increasingly reluctant to overeat. Most found it extremely difficult to gain weight, and eventually some started to drop out of the study. Only 20 made it through the requisite 200 days, achieving an average weight gain of 20-25lbs. Relieved of the high-calorie, low-exercise regimen, all but two of the inmates quickly dropped the newly acquired ballast. The pair of inmates who found it most difficult to lose weight were those who had experienced the least difficulty gaining weight in the first place. It was later discovered that both these men had a family history of obesity.

From this experiment Sims concluded that the body was remarkably well equipped to balance energy intake and output, and to reach an energy equilibrium, or "homeostasis", at which it felt naturally comfortable. What was particularly interesting was that body weight seemed somehow fixed, and was in most subjects resistant to change over the short term. The prisoners with obesity in their backgrounds were, it seemed, genetically inclined to reach homeostasis at a higher weight than were others; the high-calorie diet only helped manifest their genetic proclivity.

After hearing Sims's talk, Leibel became absorbed with the idea of finding the missing link - the signal that tells the body to eat, or not. He did not question that psychology played a role in whether or not people chose to behave in a certain way, but what interested him were the forces that drove that psychology. Genetics, he felt certain, played an important role in determining body weight regulation in humans, just as it did in mice. And there was growing circumstantial evidence to back the genetic theory, notably in studies of adopted children. Identical twins tend to have remarkably similar body mass indexes, far more similar than do siblings or even fraternal twins. This is true even for identical twins separated at birth and raised far apart in different adoptive families. The BMI (body mass index) of adopted children usually correlates nicely with that of their biological parents, but not with that of their adoptive parents. This strongly suggests that genetics, not "psychology", play the larger role in human obesity. Leibel began a painstaking search for the elusive satiety factor in the adipose tissue of normal mice.

Leibel understood the physiology of obesity, the cell physiology, and had thought through the underlying scientific problem. Friedman was at the time mastering the latest techniques in molecular biology. He had the tools for the search.

Locating a gene in a mammalian genome without knowing its protein product is something like finding the home of a reclusive uncle who lists his address as "Someplace, USA". A complete human genetic map was more than a decade away when Leibel and Friedman started their hunt for the ob gene in 1986. The team at Rockefeller spent six years narrowing the location of the ob gene to between two markers a few hundred thousand base pairs apart. Then they narrowed the field to four genes that lay inside the area where they expected ob to lie. Ultimately, a protein was located that had all the makings of Coleman's satiety factor: a molecule produced in the fat, coded for by a gene that was mutant in ob mice. "That moment was the closest thing to a religious experience I've ever had," says Friedman of the successful completion of the final test.

His team spent the next six months learning everything they could about the ob gene and its mutations, and located its human counterpart, a slightly different version they called Ob. "Positional Cloning of the Mouse Obese Gene and its Human Homologue" appeared as a cover story in the journal Nature on December 1 1994, one day after Friedman had filed for a patent.

The Nobel prize-winning biologist Roger Guillemin once told Friedman that, in a rational world, the obese gene would be renamed lepto, from the Greek word for "thin". It might be considered a gene for thinness, in the sense that mice grow fat without a properly working copy. Friedman picked up on Guillemin's suggestion and christened the ob gene product "leptin". The great hope, of course, was that leptin would work as an appetite inhibitor in humans. The first step was to test it in mice.

Injected with the newly synthesised leptin, ob mice slimmed down dramatically, and normal mice, pumped with an excess of leptin, lost every gram of their body fat. Leptin, then, was the long-sought satiety factor. It was an overnight sensation. Rockefeller's switchboard ignited with callers frantic to participate in human trials of the hormone. Food writer Jeffrey Steingarten spoke for weight watchers the world over when he told a scientist he'd be willing to inject the stuff "into my eyeball" if necessary.

After months of arduous negotiations, drug giant Amgen of Thousand Oaks, California, bought the rights to leptin for an astonishing up-front $20m payment, reportedly the largest ever for a university-held patent.

But for three years scientists searched in vain for a leptin deficit in humans. Leptin deficiency, it seemed, was not a factor in human obesity; in fact, probably quite the opposite was true. Leptin is manufactured in fat cells, so it seemed logical that obese people would have, if anything, an overabundance of the hormone. And tests showed that many of them did.

There were rare exceptions. Stephen O'Rahilly, professor of metabolic medicine at Cambridge University, was the first to show that Coleman's big idea could apply to humans. Among the strangest cases he had encountered was a pair of cousins, bright and engaging children whose parents had years earlier immigrated to London from the Punjab, in Pakistan. The father and mother of each child were themselves first cousins. The older child, an eight-year-old girl, weighed nearly 190lbs (13 stone). Despite liposuction and surgery, she could no longer walk and was transported by her parents in a wheelchair. The younger child, a two-year-old boy, weighed a staggering 65lbs (4 stone).

The parents reported that at the age of four months the cousins became possessed by a voracious hunger. Like starving explorers and concentration camp survivors, the Punjabi cousins were obsessed with thoughts of food. They ate more than their siblings, more than their parents, more than anyone could believe. And still they wanted more. O'Rahilly knew immediately that this behaviour was beyond gluttony - even greedy children don't eat frozen fish fingers and paw through garbage bins. But exhaustive testing by specialists had found nothing - there was no brain lesion or thyroid tumour, no obvious genetic aberration.

O'Rahilly didn't really expect to find leptin deficiency in the Punjabi cousins, but ran the tests, anyway. The results were remarkable - the children's blood showed not a trace of leptin. The intermarriage of cousins had allowed an exceedingly rare mutation to surface. Like the ob mice, the cousins were constitutionally unable to produce leptin. O'Rahilly and his team had found the first human carriers of the obese gene mutation: these children were fat and getting fatter because their bodies were telling their brains they were starving.

Finally, leptin treatment was ready and approved. They began slowly, with a low dose injected once daily in the girl. The effect was sudden and, to the girl's parents, miraculous. For the first time in her life, she was willing to push away from the table. She began eating no more than her brothers and sisters, and sometimes less. She stopped begging for food, and slept through the night, rather than haunting the kitchen. In a year, the girl had lost 35lbs (2 stone) and was walking without assistance. The younger cousin, who began leptin treatments two years later at age four, showed similar improvement.

Since O'Rahilly and his team announced their discovery in 1997, about a dozen people worldwide have been found with the leptin mutation [ie, an absence of leptin]. Just as with ob mice, it seems humans with the Ob mutation are infertile. A Harvard scientist, Jeffrey Flier, had shown that a decline in leptin is a warning signal to the body that something is amiss, and that the response - a heightening of appetite, a reduction of fertility - is protective. The primary role of leptin, then, is not to keep us from getting fat - as Friedman had first surmised - but to keep us from getting too thin, by setting in motion the starvation response. "For one or two months people considered leptin the Great White Hope," Flier says. "But we now know that leptin is not very good at preventing people from eating too much."

Friedman, who holds a multimillion-dollar stake in the success of the drug, is now looking to see whether leptin might play an important role in maintaining weight loss. Jeff Flier is among scores of scientists researching the pathways connecting leptin to fertility and appetite: "It's well within reason that we will know enough about the pathways that affect body weight to control obesity in 10 years," he says.

Since the discovery of leptin, obesity has become one of the hottest fields in science, drawing in the hottest young scientists. Who, after all, can blame them? The worried weighty constitute the largest - and wealthiest - drug market in history.

Genetic susceptibility to obesity once implied a slow metabolism. But we now know that the overweight generally have a faster than average metabolic rate, and expend not less but more energy than do normal-weight people. Scientists now believe that a genetic inclination toward obesity manifests itself in a constitution more finely tuned to environmental triggers. Primary among these triggers is easy access to high-fat food, coupled with a sedentary lifestyle. Most, or perhaps even all, of us are susceptible to overeating and to becoming overweight. Our genes tip the balance for each of us at a different point. Some of us succumb easily, others less so.

Increasingly, technology conducts the business once performed by our bodies. A parade of labour-saving gizmos - the television remote control, the electric garage door opener, cordless phones, power steering, food processors - add up to an environment where fewer of us every year are expending the energy necessary to maintain a grip on our appetite. Andrew Prentice, of the London School of Hygiene and Tropical Medicine, says that using a cordless phone - because it relieves us from finding a stationary phone - robs us of the equivalent of a 10km walk each year. Using a television remote rather than getting up to change channels, he reckons, can add up to as much as an extra pound a year.

Appetite control is asymmetrical: our bodies are better designed to respond to hunger than to satiety. When we are inactive, controlling appetite is not instinctive; it is something we have to impose on ourselves. The less we exert ourselves, the more difficult this becomes.

In addition, humans show considerable individ ual variation in response to overeating. Generally, scientists agree that metabolic rate is a very poor predictor of obesity, but what is almost certainly a potent factor is "non-exercise activity thermogenesis", or Neat. Neat is what most of us think of as nervous energy - the fidgeting, restless pacing, maintenance of posture and other subliminal activities of daily life. For reasons not yet understood, some people sharply increase these unconscious exertions in response to overeating. James Levine, an endocrinologist at the Mayo Clinic in Minnesota, conducted a study in which 16 volunteers (including Levine himself) were overfed 1,000 calories a day for two months. On average, the volunteers gained 10lbs. But, as is often the case, the average was not particularly revealing. One subject gained only 2lbs, while another gained 16lbs. Levine sorted through a range of factors and concluded that differences in Neat levels accounted for a tenfold difference in fat storage among the volunteers.

Childhood obesity in the US jumped from 5% in 1964 to 14% in 1999. In Australia, one out of every five children is overweight. Obesity-linked "adult onset" diabetes mellitus is for the first time being reported in children and adolescents in the UK and many other countries. In 1985 Steven Gortmaker, a psychologist at Harvard Medical School, and William Dietz, a paediatrician who now heads the nutrition and physical activity division of the Centres for Disease Control and Prevention, collaborated on a landmark study of obesity and television viewing. They found a clear association between the number of hours of television a child watched and the risk of that child becoming obese or overweight. In 12- to 17-year-olds, the prevalence of obesity increased by 2% for every hour of weekly television time. A more recent study found that, while 8% of children watching one hour or less of television a day were obese, 18% of children watching four or more hours were obese. The more television children watch, the more they eat. (By comparison, even reading is a workout, at least in studies that have been done with obese children, perhaps because it engages their minds a bit more emphatically.) Television viewing prompts children to consume more food while they consume less energy, an ideal recipe for adiposity.

When children dictate family food choices, as is increasingly the case in the US, entire households are immersed in a miasma of one-dimensional sweet taste that reinforces juvenile preferences. Marketing soft, sweet and salty foods is good business, and children are the most vulnerable targets. Childhood obesity rates are highest in countries where advertising on children's television programmes is least regulated - in Australia, the US and England. Sweden and Norway maintain a virtual ban on advertising to children, and have consistently low levels of childhood obesity. Ireland, Belgium, Italy and Denmark pose restrictions on children's advertising, and are pressing the other states of the European Union to do the same. The US and other countries can afford to do no less. Public nutrition campaigns should go beyond vague recommendations to exercise and eat a balanced diet: the link between inactivity, junk food consumption and obesity should be made explicit. The food industry will lobby against these efforts, of course, claiming that they constitute "legislation of food choices".

Nancy Wright wasn't expecting miracles when she had her stomach stapled. For a while, though, she thought she'd been handed one: she lost 125lbs (nine stone) in 18 months. She bought new clothes, got a new job, and started to feel pretty good about herself. Then she hit upon the trick of melting crackers slowly on her tongue, and found she could suck down quite a few without upsetting her newly abbreviated stomach. Ten pounds have already crept back, and she is wondering where this will end. She has cause for concern: her daughter lost 90lbs (6 stone) after gastric bypass surgery, and over the past year has gained every one back. Obesity resists easy remedy for good reason - the human body evolved biochemical redundancies to protect at all costs the instinct to nourish itself.

So many of us eat convenience foods more often than we intend, many scientists contend, because we have become habituated to them. And there is strong evidence to suggest that calorie-dense food such as fast food can entrain a neurological feedback mechanism that contributes to overeating. "As we develop a full understanding of the neuro-regulation of appetite, I think the addictive nature of foods will come clear," Charles Billington, an obesity expert at the Minneapolis VA Medical Centre, told me. "And I think we will learn that these addictions can develop at various stages in life. And I think we will learn that they are very, very powerful."

Like Big Tobacco, Big Food is a cunning manipulator of public opinion. Without intervention, virtually all Americans will be overweight by 2030, and half will be obese. Other industrialised nations are not far behind. We can no longer afford to be embarrassed, or to avert our eyes from the forces underlying this tragic pandemic. Science has taught us that the obesity pandemic is less a matter of individual preferences than of societal pressures, and of the power of the institutions that impose them. We can and should resist

Ellen Ruppel Shell, 2003

This is an edited extract from The Hungry Gene: The Science Of Fat And The Future Of Thin, by Ellen Ruppel Shell, published by Atlantic Books at 17.99.