Fasting Imparts a Switch to Alternative Daily
Pathways in Liver and Muscle
The effects of fasting on peripheral circadian clocks in the liver and skeletal muscle.
The circadian clock operates as intrinsic time-keeping machinery to preserve homeostasis in response to the changing environment. While food is a known zeitgeber for clocks in peripheral tissues, it remains unclear how lack of food influences clock function. We demonstrate that the transcriptional response to fasting operates through molecular mechanisms that are distinct from time-restricted feeding regimens. First, fasting affects core clock genes and proteins, resulting in blunted rhythmicity of brain and muscle Arnt-like protein-1 (BMAL1) and REV-ERBa both in liver and skeletal muscle. Second, fasting induces a switch in temporal gene expression through dedicated fasting-sensitive transcription factors such as glucocorticoid receptor (GR), cyclic AMP responsive element binding protein (CREB), forkhead box TF class O (FOXO), TFEB, and peroxisome proliferator-activated receptors (PPARs). Third, the rhythmic genomic response to fasting is sustainable by prolonged fasting and reversible by refeeding. Thus, fasting imposes specialized dynamics of transcriptional coordination between the clock and nutrient-sensitive pathways, thereby achieving a switch to fasting-specific temporal gene regulation.
Our study shows that daily gene expression is highly responsive to fasting through temporal coordination of the circadian clock and fasting-sensitive transcription factors (TFs). This reorganization of gene regulation by fasting could prime the genome to a more permissive state to anticipate upcoming food intake and thereby drive a new rhythmic cycle of gene expression. Therefore, optimal fasting in a timed manner would be strategic to confer robust circadian oscillation that ultimately benefits health and protects against aging-associated diseases.