Fat: What the Experts Don't Know About Obesity

By Maggie Mahar, Health Beat. Posted December 5, 2008.

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 a 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 lifelong struggle. "You just have to keep falling off the horse and getting back on again," says one woman who appears in the film 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, says 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 four 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        

Rockefeller University's 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 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 Rockefeller molecular biologists who were searching the human genome for genes and mechanisms that influence how we eat.

This diversity in a small population -- 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."

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Maggie Mahar is a fellow at the Century Foundation and the author of Money-Driven Medicine: The Real Reason Health Care Costs So Much (Harper/Collins 2006).

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