Physiology and Pharmacology of BRS3 (Bombesin Receptor Subtype-3)

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Progress in FY2021 includes the following: We published in 2020 that deletion of BRS3 in MC4R neurons increased body weight/adiposity, metabolic efficiency, and food intake, and reduced insulin sensitivity. BRS3 re-expression in these neurons caused partial or no reversal of these traits. However, these observations were confounded by an obesity phenotype caused by the Mc4r-Cre allele, independent of its recombinase activity. The deletion of BRS3 in SIM1 neurons increased body weight/adiposity and food intake, but not to the levels of the global null. The re-expression of BRS3 in SIM1 neurons reduced body weight/ adiposity and food intake, but not to wild type levels. The deletion of BRS3 in either MC4R- or SIM1-expressing neurons affected body temperature, with re-expression in either population reversing the null phenotype. MK-5046, a BRS3 agonist, increases light phase body temperature in wild type, but not Brs3 null, mice and BRS3 re-expression in either population restored response to MK-5046. We conclude that BRS3 in both MC4R- and SIM1-expressing neurons contributes to regulation of body weight/adiposity, insulin sensitivity, food intake, and body temperature. In 2021 we identified preoptic area neurons expressing BRS3 (POA-BRS3) as a population whose activation increased body temperature; inversely, acute inhibition of these neurons reduced body temperature. POA-BRS3 neurons that project to either the paraventricular nucleus of the hypothalamus or the dorsomedial hypothalamus increased body temperature, heart rate, and blood pressure via the sympathetic nervous system. Long-term inactivation of POA-BRS3 neurons caused increased body temperature variability, overshooting both increases and decreases in body temperature set point, with RNA expression profiles suggesting multiple types of POA-BRS3 neurons. Thus, POA-BRS3 neuronal populations regulate body temperature and heart rate, contribute to cold defense, and fine-tune feedback control of body temperature. These findings advance understanding of homeothermy, a defining feature of mammalian biology.