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Brs3 neurons in the mouse dorsomedial hypothalamus regulate body temperature, energy expenditure, and heart rate, but not food intake

Abstract

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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The data that support the findings of this study are available from the corresponding authors on reasonable request.

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Acknowledgements

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.

Author information

R.A.P. and M.L.R. conceived and designed the study with input from M.J.K. and O.G. R.A.P. performed and analyzed the experiments. R.A.P., S.H.Z., and A.S. performed chemogenetic experiments and immunohistochemistry and counted cells. R.A.P., S.H.Z., and B.K.T. performed optogenetic and anterograde tracing experiments. C.X. generated Brs3-Cre mice and performed western blots and qRT-PCR experiments. O.G. performed indirect calorimetry experiments. V.S. and R.A.P. performed IR experiments. C.L. performed electrophysiology experiments. R.A.P. wrote the manuscript with input from M.L.R. and all other authors.

Competing interests

The authors declare no competing interests.

Correspondence to Ramón A. Piñol or Marc L. Reitman.

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Fig. 1: Brs3 neurons are differentially activated by exposure to a cold environment and by refeeding.
Fig. 2: Activation of DMHBrs3 neurons increases Tb, and activation of PVHBrs3 neurons suppresses food intake.
Fig. 3: Inhibition of DMHBrs3 neurons reduces TEE and Tb.
Fig. 4: Optogenetic activation of DMHBrs3 neurons increases Tb, TBAT, HR, and MAP, but not physical activity.
Fig. 5: Optogenetic stimulation of DMHBrs3 →RPa terminals increases Tb, possibly via glutamate.
Fig. 6: DMHBrs3→RPa neurons receive input from POA and other nuclei.
Fig. 7: DMHBrs3→RPa neurons receive inhibitory and excitatory input from the POA.