Fat Fish Yield Genetic Insights Into Human Obesity

A binge-eating fish in Mexico shares a genetic mutation found in people with insatiable appetites that leads to obesity, researchers have found.

Blind cavefish in dark underground caverns in northeastern Mexico show a mutation in the gene MC4R that makes them genetically wired to have huge appetites whenever food is available, allowing them to survive recurring cycles of starvation by building up massive amounts of fat and burning it very slowly.

"These fish are very, very fat — much fatter than surface fish," says Harvard Medical School postdoctoral researcher Nicolas Rohner. "And although they are active, their metabolism is slower."

The evolution of different metabolisms among vertebrates could provide an understanding of the causes of human obesity, the researchers suggest.

"We all know that people have different metabolisms that lead to their gaining weight under different amounts of eating," says Harvard geneticist Clifford Tabin, lead author of the study appearing in the Proceedings of the National Academies of Science.

"The work with the cavefish gives us an example in a natural setting of why and how metabolisms evolved to be different," he says.

In the thousands of centuries since they became separated from surface-dwelling fish species, cavefish have undergone several adaptations to survive their unusual environment.

Without light, they've lost their eyesight — and even their eyes — and their bodies have no pigmentation.

The low nutrient levels in the caves have made them resistant to starvation — because their genes have made them "binge" eaters on the few occasions when food is available, such as when it is swept into the caves a few times each year, the researchers explain.

Despite being hugely overweight after the food binges, the fish can live long and healthy lives, and researchers want to know how they manage that, hoping it may someday lead to help for people who are obese.

Most of the cavefish have been found to have mutations in the MC4R gene, which, in humans, is regulated by leptin, an appetite-suppressing hormone, and insulin.

"It's one of the key components in maintaining your energy balance," says study co-author Ariel Aspiras. "When people try to diet or change how much they weigh, there are regulators in your brain that try to keep you at your current body weight. MC4R is one of them."

MC4R mutations in people, identical to what is seen in many of the cavefish, have been identified as the most common single-gene mutation causing inherited obesity, the researchers point out.

"That's something that bothers me a lot — that we have to fight against this urge to eat and drink sweet and fatty things all the time and that it's because of our evolutionary history," Rohner says. "The possibility that we can find out why that is, perhaps by using these cavefish as a model system, makes me confident that one day we will find a way to resist that urge."

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