Differential Regulation of Energy Homeostasis by Hypothalamic Bombesin-Like Receptor-3 Populations

Authors

• RA Piñol
• SH Zahler
• BK Tan
• C Xiao
• O Gavrilova
• A Kravitz
• MK Krashes
• ML Reitman

Abstract

Mice lacking the orphan G protein-coupled receptor bombesin-like receptor subtype-3 (Brs3) are obese, with reduced energy expenditure and increased food intake. Brs3 is expressed in several hypothalamic regions, including the paraventricular nucleus of the hypothalamus (PVH) and dorsomedial hypothalamus (DMH), two regions pivotal in energy homeostasis. The goal of this work is to elucidate the circuitry by which Brs3 regulates energy metabolism. We measured the effect of localized injections of Brs3 agonist MK-5046 on BAT temperature in anesthetized mice. MK-5046 injections in the DMH, but not in the PVH, raised BAT temperature. We virally expressed the excitatory DREADD hM3Dq in Brs3-Cre mice, to assess the effect of acute activation of specific Brs3 subpopulations. Chemogenetic activation of DMH-Brs3 neurons increased total energy expenditure and body temperature, with no effect on physical activity or food intake. In contrast, chemogenetic activation of PVH-Brs3 neurons robustly suppressed food intake and increased body temperature only modestly. We used an optogenetic approach to corroborate these findings and untangle the underlying circuitry. Optogenetic activation of DMH-Brs3 neurons increased body temperature. To identify the projections by which DMH-Brs3 neurons drive thermogenesis, we also implanted an optic fiber over axonal projections of DMH-Brs3 neurons in brainstem rostral raphe pallidus (RPa). DMH-Brs3 -> RPa pathway stimulation increased body temperature. Thus, different hypothalamic Brs3 neurons control energy homeostasis by increasing energy expenditure and BAT temperature, and by suppressing food intake. Specifically, PVH-Brs3 neurons can robustly suppress food intake and DMH-Brs3 neurons can drive BAT-mediated thermogenesis through projections to RPa.

Scientific Focus Area: Neuroscience

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