Salk study may offer drug-free intervention to prevent obesity and diabetes

Author: 
Salk Institute for Biological Studies
05/17/2012

Scientists have long assumed that the cause of diet-induced obesity in mice is nutritional; however, the Salk findings suggest that the spreading of caloric intake through the day may contribute, as well, by perturbing metabolic pathways governed by the circadian clock and nutrient sensors.

The Salk study found the body stores fat while eating and starts to burn fat and breakdown cholesterol into beneficial bile acids only after a few hours of fasting. When eating frequently, the body continues to make and store fat, ballooning fat cells and liver cells, which can result in liver damage. Under such conditions the liver also continues to make glucose, which raises blood sugar levels. Time-restricted feeding, on the other hand, reduces production of free fat, glucose and cholesterol and makes better use of them. It cuts down fat storage and turns on fat burning mechanisms when the animals undergo daily fasting, thereby keeping the liver cells healthy and reducing overall body fat.

The daily feeding-fasting cycle activates liver enzymes that breakdown cholesterol into bile acids, spurring the metabolism of brown fat - a type of "good fat" in our body that converts extra calories to heat. Thus the body literally burns fat during fasting. The liver also shuts down glucose production for several hours, which helps lower blood glucose. The extra glucose that would have ended up in the blood - high blood sugar is a hallmark of diabetes - is instead used to build molecules that repair damaged cells and make new DNA. This helps prevent chronic inflammation, which has been implicated in the development of a number of diseases, including heart disease, cancer, stroke and Alzheimer's. Under the time-restricted feeding schedule studied by Panda's lab, such low-grade inflammation was also reduced.

"Implicit in our findings," says Panda, "is that the control of energy metabolism is a finely-tuned process that involves an intricate network of signaling and genetic pathways, including nutrient sensing mechanisms and the circadian system. Time-restricted feeding acts on these interwoven networks and moves their state toward that of a normal feeding rhythm."

Amir Zarrinpar, a co-first author on the paper from the University of California San Diego, said it was encouraging that a simple increase in daily fasting time prevented weight gain and the onset of disease. "Otherwise, this could have been only partly achieved with a number of different pills and with adverse side effects," he says.

The multimillion-dollar question is what these findings mean for humans. Public health surveys on nutrition have focused on both the quality and quantity of diet, but they have inherent flaws such as sampling bias, response bias and recall errors that make the results questionable. Thus, says Panda, with the current data it is difficult to connect when we eat, what we eat with how much weight we gain.

"The take-home message," says Panda, "is that eating at regular times during the day and overnight fasting may prove to be beneficial, but, we will have to wait for human studies to prove this."

The good news, he adds, is that most successful human lifestyle interventions were first tested in mice, so he and his team are hopeful their findings will follow suit. If following a time-restricted eating schedule can prevent weight gain by 10 to 20 percent, it will be a simple and effective lifestyle intervention to contain the obesity epidemic.

Other researchers on the study were Christopher Vollmers, Amir Zarrinpar, Luciano DiTacchio, Shubhroz Gill, Mathias Leblanc, Amandine Chaix, Matthew Joens and James A.J. Fitzpatrick, from the Salk Institute; and Eric A. Bushong and Mark H. Ellisman, of the University of California, San Diego.

This work was partially supported by the Pew Scholars Program in Biomedical Sciences, NIH grant R01DK091618 to M.M., Sanofi Discovery Innovation Grant, and Anderson Foundation support to S.P.; JSPS fellowship to M.H.; Blasker Science and Technology Grant Award to C.V.; NIH grant T32DK007202 to A.Z.; and NIGMS grant 8P41GM103412 to M.H.E.

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