Leptin receptor neurons in the dorsomedial hypothalamus input to the circadian feeding network

Salient cues, such as the rising sun or availability of food, entrain biological clocks for behavioral adaptation. The mechanisms underlying entrainment to food availability remain elusive. Using single-nucleus RNA sequencing during scheduled feeding, we identified a dorsomedial hypothalamus leptin receptor-expressing (DMH^LepR) neuron population that up-regulates circadian entrainment genes and exhibits calcium activity before an anticipated meal. Exogenous leptin, silencing, or chemogenetic stimulation of DMH^LepR neurons disrupts the development of molecular and behavioral food entrainment. Repetitive DMH^LepR neuron activation leads to the partitioning of a secondary bout of circadian locomotor activity that is in phase with the stimulation and dependent on an intact suprachiasmatic nucleus (SCN). Last, we found a DMH^LepR neuron subpopulation that projects to the SCN with the capacity to influence the phase of the circadian clock. This direct DMH^LepR-SCN connection is well situated to integrate the metabolic and circadian systems, facilitating mealtime anticipation.