Hypothalamic REV-ERBs Control Circadian Food Intake and Leptin Sensitivity [ChIP-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. Chromatin immuno-precipitation followed by high throughput sequencing (ChIP-seq) of REV-ERBalpha genomic occupancy in hypothalamic nuclei (ARC/VMH) using HA-tagged REV-ERBalpha mice as previously described in Adlanmerini, PNAS 2019 with anti-HA magnetic beads (Pierce, 888367)