Cracking the Fat Riddle

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If Kerry Sieger were a stone age hunter-gatherer instead of a 21st century molecular biologist, chances are she would have the taut, trim body of her dreams. In college, however, Sieger underwent such a dramatic weight gain that, ever since, she has been a size 6 butterfly struggling to emerge from a chrysalis of size 20 clothes. Over the years, she has tried a succession of diets–the Scarsdale diet, the Nutri/System diet, the Michael Thurmond 6-Week Body Makeover diet, even the cabbage-soup diet–but the pounds she has repeatedly lost have relentlessly crept back.

Now Sieger, 34, a research associate at a Houston-based biomedical research firm, has turned to the Atkins diet, a weight-loss program that seems to defy nutritional wisdom. Most health experts advise you to favor carbohydrates, found in everything from fruits to grains, while going easy on the protein and fat. On the Atkins diet, one is allowed to eat all the protein- and fat-drenched meat and butter one wants but must cut out cereal and bread. And if Sieger is puzzled by certain aspects of the diet–among other things, the initial phase is so low in fiber that constipation is often a problem–she finds merit in others. “I guess I’m curious to see if it works,” she says. “I’m willing to give it a try.”

Sieger is just one of the latest wave of Americans willing to try a regimen first promulgated by Dr. Robert Atkins three decades ago. His is the diet that refuses to die, slipping in and out of favor every few years, persistently bucking the skepticism of mainstream nutritionists. Could it really be, as Atkins argues, that low-fat diets, which are typically high in carbohydrates, are bad and that low-carbohydrate diets, which often contain considerable fat, are good? Is it really O.K., as Atkins advocates, to slather mayonnaise all over salmon and tuna and douse asparagus and lobster with butter while friends look on in envy? Shades of the 1973 movie Sleeper, in which Woody Allen plays a 20th century Rip Van Winkle who awakens after a couple of hundred years to a world in which fatty delights like steak and cream pies are deemed beneficial to one’s health.

Alas, Sleeper was and is a fantasy. The indictment of excessive amounts of saturated fat–the kind found in steaks and butter–as a major contributor to heart disease and stroke has not changed and seems unlikely to do so. A formidable lineup of experts holds to the low-fat approach, none more tenaciously than Dr. Dean Ornish, whose regimen prescribes no more than 10% of daily calories from fat. With the latest resurgence of the Atkins program, the clash of the two theories is sharper than ever–low fat vs. low carbs, Ornish vs. Atkins. But here is what is new and somewhat startling: there are hints that Atkins may have struck a vein of truth–hints that are intriguing enough to convince some mainstream obesity experts that the approach merits more serious consideration. “Is it just that the Atkins diet is monotonous, and so people eat fewer calories?” wonders Dr. Samuel Klein, director of the Center for Human Nutrition at Washington University in St. Louis, Mo. Or is there something more interesting going on? Something unexpected about food itself, perhaps, or the way we eat it or even what our genes have programmed us to like?

Of course, the mere suggestion that the Atkins diet and others like it are worthy of scientific attention still makes many experts bristle. Yet it is also clear that the low-fat paradigm has developed some cracks in its facade. It turns out that not all fats are bad for you. Those found in fish, nuts and certain vegetables may actually increase your chances of living a good long life. By the same token, not all diets that are low in fat are necessarily healthy–as anyone who has ever truly considered the difference between a low-fat banana cream pie and a banana could tell you.

About one thing, however, there is no dispute. As a society we are clearly in a state of nutritional crisis and in need of radical remedies. The statistics are sobering. After 30 years of seemingly solid advice aimed at lowering dietary fat, Americans have grown collectively fatter than ever. Today more than 60% of adults in the U.S. are classified as overweight or obese. So many children have become so heavy that pediatricians are now facing an epidemic of Type 2 diabetes and hypertension–diseases that are closely associated with overweight and that were unheard of among youngsters just a generation ago.

The change has been so swift and so pervasive that no simple explanation is possible. Maybe we didn’t understand all the ramifications when we jumped on the low-fat bandwagon. We also failed to factor in suburban sprawl and six-lane expressways, school cafeterias and fast-food chains, movie theaters and television, advertisers and food processors. “We live in a toxic environment,” says Kelly Brownell, director of the Yale University Center for Eating and Weight Disorders. “Physical activities have been engineered out of day-to-day life, and the food environment grows worse by the day. We took Joe Camel off the billboards, but we celebrate Ronald McDonald.”

On one level, there is no mystery about why we as a society are fat. We are fat because we consume too many calories and expend too few. Though it is true that the proportion of fat in our diet has fallen from 40% in 1990 to roughly 34% today, the calories available in the food we consume have gone up, from 3,100 calories per capita per day in the 1960s to 3,700 in the 1990s, according to the U.S. Department of Agriculture (USDA). “And that alone,” says New York University nutritionist Marion Nestle, “is sufficient to explain the obesity epidemic.”

But there is a deeper question–one that has plagued anyone who has ever struggled to take off more than a few pounds. And that is: How do some folks manage to live in the same “toxic environment” and never gain weight? Indeed, the question of why so many of us are fat is just half the puzzle. “You can just as easily flip it around,” says Jeffrey Friedman, a molecular geneticist at Rockefeller University, “and ask why–despite equal access to calories–is anyone thin?”

The quest to answer this double-sided question is in its earliest stages. Already, however, a series of fascinating insights into the biology of obesity has emerged. Behind our broadening behinds and widening waistlines, scientists say, lies a complex array of genes that, directly and indirectly, links our gut to our brain. These genes, honed by millions of years of evolution, appear to have betrayed many of us in the 21st century world.

Scientists have long suspected that human beings come into the world equipped with dozens, perhaps hundreds, of genes and associated hormones that regulate what scientists call the energy-balance equation. On one side of the equation are the calories we consume. On the other side are the calories we burn–through physical activity as well as whatever is needed just to keep the body in good working order. Anything left over gets converted to body fat.

With the notable exception of insulin, which helps the body process sugars from carbohydrates, the identity of most of the major players in this biochemical balancing act could for years only be guessed at. The first big breakthrough occurred in 1995, when the Rockefeller’s Friedman stunned the scientific world by announcing that he and his colleagues had discovered a hormone produced by fat cells that actually caused fat to melt away, at least in laboratory mice. Genetically engineered mice that lacked the gene for making this hormone developed ravenous appetites and became grossly obese. When these same mice were injected with the missing hormone, they shrugged off a third of the weight they had gained. The researchers dubbed the new hormone leptin, after leptos, which is Greek for thin.

Although leptin has since turned into something of a disappointment as an obesity treatment for humans–the vast majority of obese people turn out to have normal leptin levels–its discovery touched off a scientific gold rush that has yet to abate. Competing research teams in the U.S. and Europe have so far identified at least half a dozen other compounds that have surprising power to regulate appetite. Researchers at London’s Imperial College of Medicine showed just last month that one of those hormones, dubbed PYY3-36, actually promotes a sense of fullness after a meal.

Each of these compounds is slightly different, and scientists are just beginning to figure out how they all work together (see diagram). What is clear is that all of them are important nodes along an elaborate network of interconnecting pathways that feed into, and out of, the hypothalamus, a brain structure that is the control center for weight regulation. The body produces hormones that activate the hypothalamus. The neurons in the hypothalamus send new messages back to the body. And just like subliminal messages spliced into a filmstrip, these signals powerfully affect our behavior even when we are not aware of them.

Thus, while we read the paper or carry on a conversation, the hypothalamus–activated by leptin or some other compound–orders cells and tissues to ratchet up energy expenditure. The body responds by idly fidgeting to raise metabolic rates, or by increasing blood flow to the outer layers of the skin in an effort dissipate heat. In this way, we carry out a process known as thermogenesis, which is the body’s way of burning excess calories.

Intriguingly, some people seem to be more efficient at thermogenesis than others. Researchers led by Dr. Bradford Lowell at Beth Israel Deaconess Medical Center in Boston last month pinpointed three genes that may account for at least some of that variation. Mice that lack the genes, they reported in Science, grow grossly obese when fed a high-calorie diet enriched with fat and sucrose. By contrast, normal mice fed the same diet gain very modest amounts of weight.

The fact that obesity has genetic roots does not explain the larger mystery. If obesity is so bad for us–and there is no question it is–then why are so many people susceptible to layering on excess fat? The answer may well lie in what is referred to as the Thrifty Gene Hypothesis, which supposes that obesity genes have been maintained in the human population because they conferred an appreciable survival advantage.

Rather like the ant in an Aesop’s fable, people with thrifty genotypes–wisely, it might be argued–prepare for hard times by consuming and storing more calories than they expend. In this fashion, they create a reservoir of fat that comes in handy when food grows scarce. It’s easy to imagine that repeated famines over the course of human development practically forced the biological system for regulating weight to skew strongly toward resisting weight loss rather than protecting against weight gain.

In principle, at least, no one should ever become obese. That’s because the genetic system for regulating weight would seem to be exquisitely tuned. Researchers calculate that a man who keeps his weight stable at 175 lbs. will take in a million calories a year on average and will also expend a million calories. “Think about it,” says Dr. Michael Schwartz, head of clinical nutrition at the University of Washington in Seattle. “How do you match a million with a million? It doesn’t happen just by chance.”

Leptin, which exercises an influence on appetite and thermogenesis, is thought to be key to maintaining this balance. For as we layer on fat, we pump out more leptin, which signals the hypothalamus that it’s time to accelerate energy output and brake caloric intake. The problem is, people who gain weight have now been shown to develop a remarkable resistance to leptin’s power. The fatter they get, and the more leptin they make, the more impervious the hypothalamus becomes. Eventually the hypothalamus interprets the elevated level of leptin as normal–and forever after misreads the drops in leptin caused by weight loss as a starvation signal. This phenomenon provides a biochemical explanation for why so many of those who lose weight end up putting it back on. Our bodies, backed by millions of years of evolution, fight us at every turn.

So what causes leptin resistance? The answer may turn out to be exceedingly complicated. Not only do the other hormones of the digestive system play a role, but also researchers are learning that they must account for the influence of such mood-altering neurotransmitters as dopamine and serotonin, as well as the stress hormones adrenaline and cortisol. And then there are melanocortins, brain chemicals whose power to affect weight loss and gain is just now coming into focus.

Genes, of course, do not make us fat. They merely set up a susceptibility to gaining weight under certain conditions–and without question, those conditions are now ubiquitous. In essence, says Dr. Walter Willett of the Harvard School of Public Health, sedentary lifestyles and a cornucopia of food have transformed people into the equivalent of corn-fed cattle confined in pens. “We have created the great American feedlot,” he says.

Our Stone Age ancestors certainly did not live in a feedlot. They had to kill and butcher their meat-on-the-hoof during marathon hunts that lasted for days, sometimes weeks. They had to ramble for miles cross-country to gather wild fruits, grains and nuts and to dig underground tubers. If they wanted to eat something sweet, they had to locate a beehive, smoke out the bees and retrieve the honey, often by climbing up a tree or chopping it down.

Likewise, the components of our diet have undergone a radical change. The flesh of the wild game that made up our ancestors’ diet had just 3% to 4% fat, whereas prime beef has 30% or more. And prior to the domestication of crops such as wheat and corn, humans consumed a variety of wild grains filled with fiber, which slows digestion. The process of highly refining foods, which allows carbohydrates to be quickly absorbed by the digestive system, wasn’t widespread. As Rutgers University anthropologist Lionel Tiger puts it, human metabolism “did not evolve for prime beef, but, one would surmise, neither did it evolve to eat heaping plates of white rice and pasta.” Nor heaping plates of doughnuts and chocolate-covered croissants, for that matter.

Why, then, do we like these foods so much? For answers, researchers are once again turning to laboratory animals, which exhibit many of the same dietary proclivities we do. Rats, for example, will labor mightily to obtain a sugar pellet even after they have dined on rat chow and aren’t particularly hungry. The reason, thinks Allen Levine, director of the University of Minnesota’s obesity center, has a lot to do with sugar’s impact on mood-enhancing circuits in the brain. Sugar gives rats–and by extension humans–a buzz.

There is also reason to think that our penchant for making unhealthy choices might be enhanced by the abundance of particular foods. Consider the results of an experiment recently conducted at Philadelphia’s Monell Chemical Senses Center. Rats given one cup each of fat, protein and carbohydrate were found to make balanced diet choices, eating a tad more protein than carbohydrates and a tad more carbohydrates than fats. But rats presented with more cups of fat and carbohydrates than protein dramatically increased their consumption of the former while sharply curtailing their intake of the latter–to the point, in some cases, that the rats became protein deficient. Why would rats do this? Perhaps because their brains are hard-wired to take advantage of sudden windfalls of food, and in the wild, of course, such windfalls do not occur every day.

They do, however, in restaurants. Soft drinks are now delivered in one-liter cups, observes Judith Stern, vice president of the American Obesity Association. Even the venerable Joy of Cooking has capitulated to the trend; recipes that used to provide meals for six now feed only four. So cheap are carbohydrates and fats that supersizing costs the food industry next to nothing.

Adults are free agents. They can overeat and gain weight if they want to. But perhaps what is most disturbing about their overeating is that they are unwittingly, and in myriad ways, passing on that tendency to children. It’s not just that children pick up their parents’ bad habits. There is growing evidence that what you eat early in life can permanently boost your body’s desire for food.

If we were to start from scratch, how would we design a diet to keep our weight under control? For starters, we could concentrate on diets geared for life rather than quick and easy weight loss. “The people I see are great dieters, beautiful dieters,” says Dr. Cheryle Hart, founder and medical director of the Wellness Workshop in Spokane, Wash. “They can deny themselves, but only for so long. Then they snap. We all would.” Second, we could stop paying such close attention to every jot and tittle in the diet debate. It will take decades for researchers to unravel all the reasons we eat what we do, and why we like to eat so much of it. But a few insights are emerging that should point us in the right direction, as long as we don’t turn them into inviolable dietary laws.

Not all carbohydrates seem to have been created equal. So-called simple carbohydrates, those found in white bread and cake, are so quickly digested by the body that they trigger a very rapid rise in the levels of glucose in the blood. The pancreas releases a massive amount of insulin to mop up the excess. Soon enough, however, blood glucose levels plummet to the point where our brains may feel woozy, we become excessively hungry and are driven to eat again. Complex carbohydrates, on the other hand, particularly those rich in fiber, do not elicit the same kind of spike-and-crash response.

Researchers refer to the amount of glucose a single serving of a particular food releases in the bloodstream as its glycemic load. And there is growing evidence that we can manipulate it somewhat to control our hunger. Broccoli and peanuts, for example, have a low glycemic load, while instant rice and baked potatoes have an extremely high one. Avoiding sugar-laden processed foods and increasing the consumption of fruits and vegetables is a first step toward sensible eating, says Dr. David Ludwig, director of the Optimal Weight for Life Program at Children’s Hospital Boston. Choosing small portions of pasta and bread made from coarsely ground wheat is a good second step.

Dairy products and milk–which has been increasingly replaced by soft drinks in the diets of both children and adults–are also fast emerging as dietary “goods,” despite the fact that a 12-oz. glass of skim milk has almost as many calories as a 12-oz. can of Coke. The reason may have to do with calcium, says Michael Zemel, professor of nutrition at the University of Tennessee. In the absence of calcium, levels of the hormone calcitriol increase. Among other things, calcitriol shuts off the mechanisms that break down fat and activates those that make it.

Fats too are gaining new respect. Olives, nuts, avocados and other foods that are rich in mono- and polyunsaturated fat belong in our diets, many nutritionists believe. Not only do these good fats help lower the level of LDL, or bad, cholesterol, but they are also essential for the absorption of fat-soluble vitamins like E.

So what would an optimal postmodern diet look like? Chances are it wouldn’t look like the food pyramid, the official government guidelines released by the usda in 1992. Indeed, the food pyramid is due for an overhaul in 2003–although no one is yet willing to give any details. If Harvard’s Willett has his way, the pyramid will make a greater distinction between the types of fats and carbs we should and shouldn’t eat. Willett, unlike the usda, does not lump most carbohydrates at the pyramid’s base or all fats at the pyramid’s eat-sparingly pinnacle. In fact, Willett places good fats–those from vegetables and fish–at the base and good carbohydrates–from whole-grain versions of bread and pasta–side by side at the base. Carbohydrates with a high glycemic load join saturated fats at the top.

The question is whether the addition of these new concepts–glycemic load, a redrawn food pyramid–can restore sanity to a collective eating binge that has spiraled out of control. And if not, then what can? An appetite suppressant that makes people eat less but has no side effects? A thermogenesis pill that one can take after overindulging in ice cream?

Perhaps the future will bring better medications, at least for people who are morbidly obese. But for the broader population, the remedy must be sought elsewhere. And as we can’t change the genes we are born with, we are left with one alternative–to change the environment that our genes have proved so ill equipped to handle. We, the species that invented barbecuing, that domesticated corn and wheat and that created foie gras and French fries, have powered through a series of food revolutions, says Oxford University historian Felipe Fernandez-Armesto in his recently published book, Near a Thousand Tables (The Free Press). The purpose of the next revolution, he predicts, will be to undo the excesses of the last.

–With reporting by David Bjerklie and Sora Song/New York, Dan Cray/Los Angeles and Elisabeth Kauffman/Nashville