It may not be what you eat, but when

A series of new studies from a Penn Medicine research team shows that when you eat might be just as important as what and how much you eat in determining whether your body will convert those calories to energy or store them as unwanted fat.

The primary circadian “clock” in our brain controls our appetite. But within our bodies, tiny cells carry their own clocks, which are also tied to the 24-hour day. For example, peripheral clocks in the liver regulate glucose metabolism, and clocks in the cells of the pancreas play a role in insulin secretion.

However, little is known about how these clocks communicate with each other.

Georgios Paschos, a research associate in the lab of Garret FitzGerald, FRS director of the Institute for Translational Medicine and Therapeutics at the Perelman School of Medicine, set out to understand what role the circadian clocks of adipocytes, or fat cells, play in the storing of energy and weight regulation.

“We are more prone to store those excess calories instead of utilizing them for our energy needs when we consume them at the inappropriate time,” Paschos says.

By genetically deleting the core clock components of fat cells in test mice, the team first discovered that the altered mice gained more weight compared to normal mice. More importantly, the feeding behavior of the mutant mice changed. They began to eat more during the day. The team documented a 50 percent increase in calories consumed during daylight hours.

“Our initial observation showed us that there is this change in time when the calories were consumed but there was no change in the total amount of calories consumed throughout the day,” Paschos says.

A subsequent experiment demonstrated that normal mice also became obese when researchers restricted their access to food at night, leading the mice to eat more during the day. This behavioral change in the mice is somewhat akin to night-eating syndrome in humans, which affects many night-shift workers and also is associated with obesity.

“When we control the environmental cues that might change the behavior of the animals, and when we compare animals with dysfunctional circadian clocks to normal animals, we can make the conclusion that it’s because of lack of a functional clock that we have changes in their rhythmic behavior and parameters we can measure, one of them being feeding behavior,” Paschos says.

Still, that didn’t explain why the mutant mice were gaining more weight, since both groups were consuming the same amount of food. That made Paschos want to learn how the fatty cells were communicating with the “master clock” in the brain. Traditionally, clocks in peripheral tissues were thought to follow the lead of the “master clock.” But when the clock in fat cells was broken, it effectively threw off the hypothalamic rhythm. This suggested, for the first time, that fatty tissue in animals is more metabolically active than previously thought in determining eating behaviors.

Tissue samples taken from the mutant mice during daytime feedings confirmed they had lower levels of two key polyunsaturated fatty acids: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are also commonly associated with fish oils. Fatty acids are synthesized by fat cells and released into the blood stream. They signal reserve energy levels to the brain, helping regulate food intake.

Our study suggests that when eating at the inappropriate time, the calories consumed are utilized in a different way compared to the calories that are consumed at an appropriate time."

When researchers supplemented the diet of the mutant mice with EPA and DHA, the animals didn’t gain as much weight as the control group.

“Our study suggests that when eating at the inappropriate time, the calories consumed are utilized in a different way compared to the calories that are consumed at an appropriate time,” Paschos says.

FitzGerald and Paschos’s work was supported by the National Heart, Lung, and Blood Institute and the Medical Research Council. Co-authors include Salam Ibrahim, Wen-Liang Song, Takeshige Kunieda, Gregory Grant, Teresa M. Reyes, Fenfen Wang, and John A. Lawson, all from Penn. The research was published in Nature Medicine.

Paschos says they’ve only started to scratch the surface, and additional animal studies will help gain a better understanding of new behavioral practices and therapies to help human night workers and others synchronize their clocks without the detrimental effects of unwanted weight gain.

“Potentially targeting pharmacologically the circadian clock might also be a way by which we can trick our body into understanding a different time,” he says.

This, no doubt, will mean many more long nights spent in the lab collecting and measuring blood and tissue samples. But whenever he feels hungry, Paschos needs only to steal a glance at his chubby, nocturnal test subjects to fight the urge to eat.

“A snack is always tempting, but it certainly is not something that’s a healthy practice,” he says.