The ARC neurons play a crucial role in the regulation of energy homeostasis.

Recent single-cell RNA sequencing study suggested that CRABP1 expressing neurons in the arcuate nucleus (ARC neurons) were a distinct group of neurons. However, the physiological role of ARC neurons remains unexplored. Here, we demonstrated that ARC neurons played a crucial role in regulation of energy homeostasis in male mice. Ablation of ARC neurons resulted in obesity and a diabetic phenotype in mice. By employing chemogenetic or optogenetic manipulation techniques, the inhibition and activation of ARC neurons resulted in an increase and decrease in food intake, respectively. The axon terminals from these ARC neurons project to several brain regions implicated in feeding regulation such as PVH, BNST, PBN, and NTS. Optogenetic manipulation of these axons within these brain regions resulted in significant alterations of food intake behavior in mice. Furthermore, the electrophysiological studies demonstrated that the activation of ARC neurons induces depolarization in POMC neurons in the hypothalamus. The hormone stimulation studies showed that most of the ARC neurons respond to insulin. Collectively, our findings demonstrate that ARC neurons represent a distinct neuronal subtype involved in energy homeostasis regulation.