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

2014财年的进展包括： 为了研究BRS-3作用的特定细胞、部位、组织和递质，我们产生了BRS-3小鼠。这是一个非常重要的工具，使条件删除研究成为可能。我们也有一个由Brs3驱动的Cre重组酶敲击小鼠，尽管我们不知道Cre表达是否足够高，对小鼠有用。 我们发表的文章指出，如果将体温作为体力活动水平和明/暗阶段的函数进行分析，那么降低的体温更容易被检测到。体力活动水平与4分钟后的体温相关性最好。Brs3基因缺失的代谢表型不是由于棕色脂肪组织功能的内在受损，也不是由于交感信号从大脑到棕色脂肪组织的交流，因为Brs3基因缺失的小鼠对应激、急性寒冷暴露和β3肾上腺素能激活具有完整的生热反应，而Brs3基因缺失的小鼠喜欢更凉爽的环境。用BRS-3激动剂MK-5046治疗可以提高野生型小鼠的棕色脂肪组织温度和体温，但不会增加Brs3基因缺失的小鼠的体温。下丘脑内注入MK-5046可提高体温。这些数据表明，BRS-3对体温的调节是通过交感传出神经上游的中枢机制来实现的。Brs3基因缺失小鼠的体温降低是由于能量平衡调节的改变影响了体温的更高中心调节，而不是棕色脂肪组织的固有缺陷。

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.