Bombesin-like receptor 3 (BRS3) is an orphan G-protein-coupled receptor that regulates energy homeostasis and heart rate. We report that acute activation of Brs3-expressing neurons in the dorsomedial hypothalamus (DMHBrs3) increased body temperature (Tb), brown adipose tissue temperature, energy expenditure, heart rate, and blood pressure, with no effect on food intake or physical activity. Conversely, activation of Brs3 neurons in the paraventricular nucleus of the hypothalamus had no effect on Tb or energy expenditure, but suppressed food intake. Inhibition of DMHBrs3 neurons decreased Tb and energy expenditure, suggesting a necessary role in Tb regulation. We found that the preoptic area provides major input (excitatory and inhibitory) to DMHBrs3 neurons. Optogenetic stimulation of DMHBrs3 projections to the raphe pallidus increased Tb. Thus, DMHBrs3→raphe pallidus neurons regulate Tb, energy expenditure, and heart rate, and Brs3 neurons in the paraventricular nucleus of the hypothalamus regulate food intake. Brs3 expression is a useful marker for delineating energy metabolism regulatory circuitry.
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We thank A. Kravitz for input throughout the project and critical reading of the manuscript, A. Franks for assistance with animal husbandry, Y. Huang and Y. Ma for assistance with surgeries, and A. Noguchi and D. Springer of the NHLBI Murine Phenotyping Core for the cardiovascular telemetry implantation surgeries. S. Sternson provided the AAV-ChR plasmid construct and R. Neve (Massachusetts General Hospital, Boston, MA), provided HSVs. MK-5046 was generously donated by Merck. Rabies virus was obtained from the GT3 Core Facility of the Salk Institute, which was funded by NIH-NCI CCSG: P30 014195 and NINDS R24 Core Grant and funding from NEI. This research was supported by the Intramural Research Program (DK075057, DK075062, and DK075063 to M.L.R.; DK07002 to M.J.K.) of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH.