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

Abstract

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.

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

“…S3G). However, the Glp1r DMH neurons in our study also expressed the leptin receptor gene, Lepr, and so may correspond to a previously identified population of DMH inhibitory neurons which co-express Glp1r and Lepr 85 . Lepr+ DMH neurons inhibit AgRP neurons in response to external food cues to reinforce food-seeking behavior 18,86 .…”

“…One possibility is that the Glp1r + DMH neurons rapidly inhibit AgRP neurons in response to external food cues, as previously reported of DMH Lepr + neurons 17 , potentially to reinforce food-seeking behavior (Berrios et al, 2021). Accordingly, a recent single-cell RNA-seq analysis of DMH neurons showed that expression Glp1r and Lepr are highly co-localized 70 . However, unlike the Lepr + DMH neurons, the Trh Arc neurons characterized in our study received little if any synaptic input from the lateral hypothalamus (Fig.…”

Leptin signaling and its central role in energy homeostasis

“…Furthermore, DMH LepRb neurons that project to the suprachiasmatic nucleus exhibit calcium activity prior to an anticipated meal. These neurons serve as a crucial link between the metabolic and circadian systems, thus facilitating mealtime anticipation (Tang et al, 2023). The sympathetic nervous system (SNS) mediates the cardiovascular and thermogenic effects of leptin within the DMH.…”