"Fat prejudice is the primary impediment to understanding - or wanting to understand what obesity is all about," says a public health nurse who appears in "Fat: What No One Is Telling You," a 2007 PBS home video documentary.

In the first installment of this post, I explained how little physicians know about what causes obesity - in part because, as this nurse points out, "blaming the victim has stood in the way of understanding." Here, I am reminded of how, in the past, we blamed patients suffering from depression and other forms of mental illness. For centuries, this prejudice stood in the way of understanding that mood disorders are caused by a flaw in chemistry, not character

In "Fat," patients describe how even some doctors treat them with contempt. "When I went to get a Pap smear, the doctor said, 'You're too fat; come back when you've lost weight,'" one woman recalls.

The documentary also points out that "while everyone dies . . . it should perhaps come as no surprise that in our society, obese people are blamed for dying. If a thin patient comes into the hospital, has a heart attack, and dies, cause of death is labeled 'heart disease', a public health nurse who appears in the film tells the filmmakers. "If an obese patient has a heart attack and dies, cause of death is 'obesity'."

Nevertheless, despite the bias, today scientists have begun to look past the old-fashioned notion that obesity is merely a matter of gluttony, and have made real progress in beginning to understand a terribly complicated chronic disease.

Granted, obesity doesn't look like "a subtle disease," acknowledges Harvard's Dr. Lee Kaplan, who heads the Weight Reduction Program at Mass General Hospital. Conventional wisdom says that if you put too much food in your mouth, and don't exercise enough, you'll wind up fat. Period.

As is so often the case, the conventional wisdom is wrong. The truth is that "more than 400 genes are involved in weight regulation. And that doesn't include the environmental factors," Kaplan points out. The experts report that some people eat rich, fatty foods, never exercise, and remain thin. Others exercise daily, diet religiously and are seriously overweight. Of course many overweight people who need to lose 20 or 25 pounds take it off and keep it off. But they are not obese - they are not fighting a chronic condition.

Ninety-five percent of obese patients who remain in medically supervised treatment regain whatever pounds they lose. Physicians don't know why. They have not been able to figure out how to help these patients because medical science has not yet sliced through the tangle of genetic, metabolic, social, psychological and environmental factors that cause obesity.

A Unique Disease - the Body Undermines the Cure

What we do know is that "Obesity is the one disease where your body fights the cure," says Dr. Michael Rosenbaum, a Columbia University researcher working on an NIH-funded study on weight control.

By and large, the body is programmed to help you heal. But not in this case. People think that dieting is "a matter of choice," says Arthur Frank, medical director of the George Washington University Weight Management Program. But in fact, losing weight requires overcoming powerful brain signals that are working against you.

If you have ever dieted you may already know that, once you lose some weight, your metabolism slows down and you burn fewer calories. For all your body knows, you are stranded on a desert island, starving to death. So it tries to "help." The brain is wired to eat and store fat to protect against starvation. In fact, when you lose weight, the human body has redundant systems to try to save you. That's how the human species has survived.

In "Wired to Eat," a 2005 article published in MIT Technology Review, Jeffrey Friedman, an obesity researcher at Rockefeller University, explains that the mechanism that drives us to eat is located in the hypothalamus at the base of the brain, where two types of neurons appear to be the chief regulators of appetite. These neurons tell us when we're hungry and when we're not. The so-called NPY neuron stimulates hunger, and the POMC inhibits appetite. Each neuron is turned up or down by chemicals that wash over them. "A dominant factor in controlling weight is this basic neural circuit," says Friedman.

The chief chemical involved is leptin, a hormone produced by fat cells in the belly. When people gain weight, fat cells increase the levels of leptin, and as leptin washes over the POMC neuron, their appetite is suppressed. When people start to lose weight, body fat is reduced, which decreases the levels of leptin. Less leptin means the POMC turns down and the NPY neuron predominates, which ramps up hunger. Other chemicals - fats, sugars, and neural transmitters - also influence the actions of these neurons, but leptin seems to be the key.

Friedman is famous for his 1994 discovery of the gene that codes for leptin. And for a brief moment in the mid-1990s, the MIT Technology Review explains, "leptin seemed to be a potential wonder cure for obesity." Researchers hoped that leptin injection would turn up the POMC neuron that inhibits hunger. But leptin injections work for only a small percentage of the obese. It turns out that the majority [of obese people] do produce leptin, but their bodies actually resist the effects of the hormone by blocking its ability to turn up the hunger-suppressing action of the POMC neuron. So their appetites remain large, and they keep eating - and gaining weight - until they reach the point at which the resistance stops. Where that point lies, Friedman believes, is determined by genetic makeup.

Some people appear to be hardwired to be particularly ravenous. When access to food is unlimited, say hunger-gene experts, these people can will themselves to eat less, but their efforts will almost inevitably be overridden by the far more powerful force of genetics. Studies show that invariably, weight loss is followed by weight gain, making obesity a life-long struggle. "You just have to keep falling off the horse and getting back on again," says one woman who appears in "Fat." A physician in the film points out that trying to continue eating less is like trying to run upstairs without breathing faster. "You can do it for a while, but not for that long."

This explains why appetite suppressants have a minimal effect in helping obese patients according to Dr. Robert Lustig of the Division of Pediatric Endocrinology at the University of California, San Francisco. "These medications become less and less effective after just 4 months," Lustig explains. This is not because of a lack of compliance on the part of the patient, but rather due to leptin resistance, which persists even in the face of pharmacotherapy. When appetite suppressants foil one set of receptors, another mechanism kicks in, and hunger returns."

Looking for the Needle in a Small Gene Pool

Friedman did some of his most important obesity research on Kosrae, a tiny volcanic island in the Pacific Ocean some 4,670 kilometers southwest of Hawaii. There, he led a Rockefeller University team that worked in a joint project with the Kosrae State health authorities and the U.S. Department of Health and Human Services to discover why not everyone on the island was overweight.

Until the United States took control of Kosrae and the rest of Micronesia after World War II and began shipping in canned and processed foods, the people of this island were predominately lean - eating fish, bananas, coconuts, and taro. Most islanders lived a near-subsistence life, suffering through frequent droughts and stormy seasons that decimated crops. And they stayed thin.

But after World War II, their diet changed. San Francisco Chronicle reporter David Ewing Duncan visited the island in 2005, and describes grocery store shelves stocked with "Frosted Flakes, pork and beans, canned peas, soft drinks, and Spam . . . Today well over half of the adult population is overweight," he observes. This comes as no shock; we know that as environment changes, and foods high in carbs and fat become widely available, an entire population is likely to gain weight.

The surprise is that some on the island remained lean despite the change in diet. And this is what attracted molecular biologists at Rockefeller searching the human genome for genes and mechanisms that influence how we eat.

This diversity in a small population, with only 7,600 people on an isolated island where most people are descended from a few families, is what intrigued Friedman. Having just a few genetic lineages on the island means that each person's genomic makeup is far more similar to his or her compatriots' than, say, an American's would be. "Looking for a gene is like searching for a needle in a haystack," he says. "On Kosrae, the small gene pool makes the haystack smaller."

The MIT Technology Review explains Friedman came to believe that the Kosraeans' ballooning weight is a manifestation of what geneticist James Neel in 1962 dubbed the 'thrifty gene' theory. Neel posited that in an environment prone to famine, hunter-gatherers gained a selective advantage if their genes predisposed them to storing fat when food was available. Those with such 'thrifty genes' were more likely to survive famines and pass on their genes. But in modern times, the thrifty gene has proved a liability.

"The theory also posits that people who lived in early agricultural societies, such as those in the Fertile Crescent in the Middle East, had a steady supply of food from plants and domesticated animals and thus didn't need to store fat. So in our world today, people with lean genes are protected from obesity, and those with fat genes are at the mercy of DNA."

"Why leptin resistance occurs in some people is poorly understood, Friedman says. It may be a relic of the thrifty-gene response, ramping up appetite in those whose ancestors lacked adequate food. The Rockefeller team measured leptin levels in the Kosraean population; Friedman is using that data to help correlate leptin resistance with genes that might be responsible for it. According to Friedman, each of us has a 'set point' of hunger and satiation, which we inherited from our individual forebears. We are born with this setting, and we are driven to keep eating until we reach it."

"People whose ancestors, like most Kosraens', had to work hard to get enough to eat, had their hunger-volume - analogous to a specific setting on a radio dial - turned up to 8 or 10." Duncan adds. "Those whose ancestors had plenty of food - for instance, the agriculturists of the Fertile Crescent and Europe, and parts of India and China, people who have basically had stable food supplies for as many as 10,000 years - have inherited a setting of two or three."

Friedman concedes that more work is needed to understand the role of exercise in weight gain. But, according to the MIT Technology Review, he does believe that "the weight increases of the past 20 years in the United States represent a steady progression of people eating enough food to reach their set points, rather than a sudden spike in bad eating habits or more sitting around. What really intrigues Friedman is why everyone doesn't get chubby when there is plenty to eat. Analyses show that the number of lean people has remained steady for the past 30 years, he says. 'One's size is not an environmental effect. Nor is it a matter of willpower.'"

There is of course much money to be made if entrepreneurs can convince the obese that they have the secret to weight loss. As Duncan notes, "the diet industry [is] skeptical of Friedman's claim that obesity is as over-determined [as he claims. The industry] insists that people can overcome the hunger impulse and trim down with healthy diets and reduced calories. Friedman says this is true, but that even a heavy person in most cases can lose only 10 or 20 pounds and keep it off. But even a small amount of weight loss can be healthy, he says. 'You can lose more for a period of time,' he says, but the biology will eventually force you to eat in most cases, and 'you will regain the weight.'"

"Friedman acknowledges that what he suggests is counterintuitive, since people can resist jelly beans up to a point. But he insists that, for the majority of the obese, free will in weight control is an illusion. 'This is a way of thinking that needs to change.'"

One might wonder why the "thrifty gene" has survived. After all, how many Americans die because they don't get enough food? Granted, many of America's poor are malnourished, which in turn leads to diseases that can be fatal, few succumb because they simply can't get enough calories.

But as the documentary "Fat," points out , Americans "have gone from having very little to eat to being able to eat a lot - with a few bucks in our pocket - in just 75 years.

Panning a fast-food restaurant, the film points out, "how many calories you can get for just four bucks." This wasn't true during the Great Depression of the 1930s. Indeed, the film's narrator observes "there are millions of people who are here today who wouldn't have been here 60 years ago" because they couldn't have "gotten this much food for that amount of money in yesterday's dollars."

Little wonder that the brain still sounds an alarm when we lose weight.

What We Are Learning From Gastric Bypass Surgery

And "leptin resistance" is just one of many mechanisms that protects us. "The gut has a nervous system - and a mind of its own - that decides what and how much we eat," says Michael Gershon a bowel expert at Columbia University who appears in "Fat."

At Mass General, Dr. Lee Kaplan agrees: "We have two brains - in the stomach and 'upstairs.' The brain in the gut can disturb the brain in the head."

"Neuro-chemical signals that flow between the two brains," Kaplan adds and we have discovered that gastric bypass surgery (a.k.a. "stomach-stapling") interrupts that flow.

Until recently, physicians believed that patients lost weight because the surgery reduced the size of the stomach, forcing them to eat less. But once again, it's not that simple. Researchers performing gastric bypass surgery on rats have discovered that the surgery severs nerves in the bowel that communicate with the brain - and that this is tied to weight loss.

Today, the surgery is giving researchers valuable new information about how the brain and gut manage obesity. "In the next 5 or 10 years, we'll find that there are many, many other things we didn't know," Kaplan predicts.

"Gastric bypass surgery is not a solution for obesity - it's only appropriate for the sickest of our patients," he adds. "But it's given us an enormous hope that, through what we learn, we'll be able to solve the problem."