Leptin-responsive dorsomedial hypothalamic neurons link circadian and metabolic systems to govern food anticipation [snRNA-seq]

In contrast to light-dependent entrainment of the central circadian pacemaker, the molecular and neural underpinnings of entrainment by non-photic cues, such as food, remain unclear. Using single-nucleus RNA-sequencing, we identified a leptin receptor (LepR) positive neuronal population in the dorsomedial hypothalamus (DMH) that is responsive to scheduled feeding (SF). During SF, DMH LepR neuron activity precedes an impending meal. Mis-timed exogenous leptin administration or chemogenetic activation of DMH LepR neurons inhibits both neuronal and behavioral food anticipatory activities. Further, repetitive chemogenetic activation of DMH LepR neurons partitions a secondary bout of circadian locomotor activity in phase with the stimulation. This work places DMH LepR neurons as an essential integrator of food entrainment, and positions leptin as a critical central mediator of this circadian response. Overall design: We performed single nuclei RNA-seq of the dorsomedial hypothalamus and suprachiasmatic nucleus of Lepr-cre::tdTomato mice under either ad libitum, overnight fasted, of scheduled feeding diets.