Hypothalamic REV-ERBs Control Circadian Food Intake and Leptin Sensitivity [RNA-seq]

Obesity occurs when energy expenditure is outweighed by food intake. Tuberal hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), regulate feeding amount as well as energy expenditure. Here we report that mice lacking circadian nuclear receptors REV-ERBa and b in the tuberal hypothalamus (HDKO) gain excessive weight on an obesogenic diet due both to decreased energy expenditure and increased food consumption during the light phase. Moreover, rebound food intake after fasting is markedly increased in HDKO mice. Integrative transcriptomic and cistromic analyses revealed that such disruption in feeding behavior is due to perturbed REV-ERB-dependent leptin signaling in the ARC. Indeed, in vivo leptin sensitivity is impaired in HDKO mice on an obesogenic diet in a circadian manner. Thus, REV-ERBs play a crucial role in hypothalamic regulation of food intake and circadian leptin sensitivity in diet-induced obesity. Transcriptomic profiling (RNA-seq) of punched-out hypothalamic nuclei (ARC or VMH) harvested from control or REV-ERBS (alpha and beta) DKKO mice on control treated with either normal chow, high fat diet (HFD), fasting, refeeding, or treated with leptin. Library was prepared with Illumina Truseq kit and sequenced on Illumina Hiseq 4000 sequencer.