AN ILL-SET CLOCK PROMOTES FATTY LIVER DISEASE
Abnormal sleep patterns, such as those of shift-workers, can be risk factors for obesity and diabetes. Investigators have known for decades that fat production by the liver runs on a 24-hour cycle, similar to the sleep-wake cycle. Recently, Mitch Lazar, MD, PhD, director of the Institute for Diabetes, Obesity, and Metabolism, and colleagues have identified two players in that cyclic fat production: Rev-erb and HDAC3. If either of the proteins stops working, the cycles do not occur, and the liver fills with fat. However, mice lacking HDAC3, are protected from diabetes-like symptoms, even though their livers are filled with fat. Lazar’s group thinks the reason for that paradox is how the fat is stored. When the on-off cycle of HDAC3 was absent, the livers filled with fat but sequestered it in tiny droplets within liver cells—essentially protecting the organism from the excess lipids.
RESETTING THE CLOCK TO RESTORE HEALTH
In an unexpected twist, John Hogenesch, PhD, associate professor of Pharmacology, and colleagues found that information travels both directions between the clock and cell pathways. He says that clock biologists expected the clock to influence metabolic pathways, but when his group performed a large genome screen they also found that metabolic pathways influenced the clock. That might mean that in the future physicians may be able to use small molecules that inhibit or stimulate these biological processes to influence a person’s clock when it gets out of sync due to jetlag or shift work.
IT'S NOT JUST WHAT YOU EAT, BUT WHEN YOU EAT IT
Fat cells store excess energy and signal these levels to the brain. Georgios Paschos PhD, research associate in the lab of Garret FitzGerald, MD, FRS director of the Institute for Translational Medicine and Therapeutics, found that deletion of the clock gene Arntl, also known as Bmal1, in fat cells, causes mice to become obese, with a shift in the timing of when this nocturnal species normally eats. These findings shed light on the complex causes of obesity in humans. They were surprised in two respects. “The first is that a relatively modest shift in food consumption into what is normally the rest period for mice can favor energy storage,” says Paschos. “Our mice became obese without consuming more calories.” Indeed, the Penn researchers could also cause obesity in normal mice by replicating the altered pattern of food consumption observed in mice with a broken clock in their fat cells.
This behavioral change in the mice is somewhat akin to night-eating syndrome in humans, also associated with obesity and originally described by Penn’s Albert Stunkard, MD in 1955.