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

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Progress in FY2014 includes the following: In order to study the specific cells, sites, tissues, and transmitters by which BRS-3 acts, we have generated floxed Brs3 mouse. This is a hugely important tool, making possible studies with conditional deletion. We also have a knock in mouse with Cre recombinase driven by Brs3, although we do not know if the Cre expression is high enough for the mouse to be useful. We published that the reduced body temperature is more readily detected if body temperature is analyzed as a function of physical activity level and light/dark phase. Physical activity level correlated best with body temperature 4 minutes later. The Brs3 null metabolic phenotype is not due to intrinsically impaired brown adipose tissue function or in the communication of sympathetic signals from the brain to brown adipose tissue, since Brs3 null mice have intact thermogenic responses to stress, acute cold exposure, and beta3-adrenergic activation, and Brs3 null mice prefer a cooler environment. Treatment with the BRS-3 agonist MK-5046 increased brown adipose tissue temperature and body temperature in wild-type but not Brs3 null mice. Intrahypothalamic infusion of MK-5046 increased body temperature. These data indicate that BRS-3 regulation of body temperature is via a central mechanism, upstream of sympathetic efferents. The reduced body temperature in Brs3 null mice is due to altered regulation of energy homeostasis affecting higher center regulation of body temperature, rather than an intrinsic defect in brown adipose tissue.