Originally created 05/10/04

Isolated obese populations help search for genetic influences

On the Pacific island of Kosrae, scientists hope to find answers to one of the biggest mysteries about obesity: What genes nudge some people toward getting fat?

Many studies indicate genes influence weight, although they don't control it completely. But identifying the responsible genes is difficult, because in most cases many genes work together to promote obesity, each exerting such a small effect that it's hard to detect.

So researchers have turned to confined populations that are prone to obesity. The idea is that since such a group draws its genes from a relatively restricted gene pool, the genetic variants responsible for obesity should be easier to find.

By identifying such variants, scientists hope to get a better understanding of the biological causes of obesity in the general population. That in turn could lead to better treatments, or at least a way to identify people at risk of becoming obese so that they could take preventive steps.

On Kosrae, scientists might also be able to study the other side of the coin: When calories are cheap and readily available, are there gene variants that help keep some people lean?

That's one interest of Dr. Jeffrey Friedman, a Howard Hughes Medical Institute investigator at Rockefeller University in New York, who with colleagues Dr. Marcus Stoffel and Dr. Jan Breslow has been studying the people of Kosrae for a decade.

In fact, Friedman believes that obesity-promoting and leanness-promoting genetic variants in today's residents of Kosrae - and elsewhere - might be traceable to what their ancestors were experiencing thousands of years ago.

His argument builds on the so-called "thrifty gene hypothesis" proposed in the early 1960s. That hypothesis suggested that in an environment prone to famines, hunter-gatherers would gain an advantage if their genes predisposed them to obesity. That way, they could save up calories to survive food shortages.

Since people with these "thrifty genes" would be more likely to survive famines, those genes would be passed on to modern-day descendants.

But in an environment of plentiful food and little risk of starvation, thrifty genes could be a liability. Friedman suggests that could have been the situation for ancient populations in the Fertile Crescent of the Middle East.

Indeed, Fertile Crescent people would benefit from gene variants that would encourage them to resist obesity despite the availability of food, he argues. And presumably, those variants would still persist today alongside the obesity-promoting variants from humankind's hunter-gatherer legacy.

Could it be, Friedman asks, that obese people carry the "hunter-gatherer" genes and lean people carry "Fertile Crescent" genes?

He's studying Kosrae to test that theory. There, about half the adults are obese, and another 30 percent are overweight.

Residents of the island were living as hunter-gatherers when first sighted by Westerners in the 1800s, he said. Even then, some explorers reported seeing women who had a tendency to be fat, but the obesity rate was nothing like today.

Later, islanders intermarried with visiting whalers who settled there. So today's population draws genes from its native pool and the outsiders. But it wasn't until after World War II and the introduction of a Western diet, Friedman says, that being overweight became the norm.

Friedman and colleagues plan to test the possibility that obese residents tend to carry native Micronesian gene variants while the lean inhabitants tend to carry Caucasian variants of the same genes.

Working with local health authorities, the scientists have built up a huge family tree and DNA bank involving thousands of people on the island - most of its adults. And the hunt for genes is under way.

On the Net:

Obesity genetics: www.cdc.gov/genomics/info/perspectives/obesity.htm