There have been many studies that have demonstrated how the circadian clock controls various aspects of homeostasis, and how organs coordinate their function. In the liver, the circadian clock regulates the metabolism of drugs and energy sources, including glucose, lipids, and proteins. A new study led by researchers at the Institute for Research in Biomedicine (IRB Barcelona) reveals the mechanisms behind the circadian clock of the liver.

The findings are published in the journal Science Advances in a paper titled, “Integration of feeding behavior by the liver circadian clock reveals network dependency of metabolic rhythms,” and led by Salvador Aznar-Benitah, PhD, group leader at IRB Barcelona.

“The mammalian circadian clock, expressed throughout the brain and body, controls daily metabolic homeostasis,” the researchers wrote. “Clock function in peripheral tissues is required, but not sufficient, for this task. Because of the lack of specialized animal models, it is unclear how tissue clocks interact with extrinsic signals to drive molecular oscillations. Here, we isolated the interaction between feeding and the liver clock by reconstituting Bmal1 exclusively in hepatocytes (Liver-RE), in otherwise clock-less mice, and controlling timing of food intake. We found that the cooperative action of BMAL1 and the transcription factor CEBPB regulates daily liver metabolic transcriptional programs.”

“It’s a very nice discovery because it is the first demonstration of the need for communication between the circadian clocks of tissues and organs outside the brain, and we can see that this communication between muscle and liver is altered by aging,” said Aznar-Benitah. “When we get older, cells stop obeying the biological clock and begin to perform functions in a non-optimal manner, leading to errors that cause tissues to age.”

This work has been a collaboration with the laboratories headed by Paolo Sassone-Corsi, PhD, at the University of California, Irvine, Pura Muñoz-Cánoves, PhD, at Pompeu Fabra University, and Kenneth A. Dyar, PhD, at the Helmholtz Zentrum München.

Their findings reveal that the liver is not autonomous in the metabolism of fats and that it is a muscle that sends the message that it is time to switch on fatty acid metabolism and how it should go about this. “We didn’t expect to find this connection between the liver and muscle because it wasn’t known previously, but, on second thought, it makes complete sense that fat management is coordinated by one of its main consumers,” explained Aznar-Benitah.