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Feast, famine and the genetics of obesity

In addition to fast food, desk jobs and inertia, there is one more thing to blame for unwanted pounds—our genome, which has apparently not caught up with the fact that we no longer live in the Stone Age. That is one conclusion drawn by researchers in the lab of Marc Montminy, who recently showed that mice lacking a gene regulating energy balance are protected from weight gain, even on a high-fat diet.

In a study published in Nature, Montminy and his team report that a gene known as CRTC3 decreases energy expenditure by fat cells. "Ideas about obesity are based on concepts of feast or famine," he says. "As humans, we developed ways of coping with famine by expressing genes like CRTC3 to slow the rate of fat burning. Individuals with these active "thrifty genes" had an advantage—they could survive long periods without food." In the 21st century, however, those genes have become a liability.

To analyze its role in fat metabolism, the researchers engineered mice lacking the CRTC3 gene and put them on diets of varying fat composition. Normal and CRTC3 gene "knockout" mice appeared similar when fed a moderate fat diet. But when fed the mouse version of the Philly cheese steak diet, only the normal mice became obese. "The CRTC3 knockout mice were leaner and protected from obesity," reports Montminy. "They also had about twice as many brown fat cells as normal mice."

Brown fat tissue actually burns white fat tissue to generate heat as a way to maintain body temperature. In fact, some evidence suggests that humans with a genetic propensity to leanness have more brown fat cells than "ample" individuals do. As desirable as that trait may seem in a "super-size me" world, those folks likely had a pretty tough time in the Paleolithic era.

Although the researchers found that CRTC3 loss also perturbs how all fat cells respond to brain signals controlling energy expenditure, they remain particularly intrigued by the brown fat connection. "CRTC3 could be a switch controlling the number of brown fat cells," says Montminy. "That is key because if you could make more brown adipocytes, you could potentially control obesity."