下丘脑PKA-RIIβ信号通路调控脂肪组织褐变的机制研究

PKA是重要细胞信号传导分子，调控机体脂肪代谢稳态。含有RIIβ亚基的PKA分布在脂肪细胞与神经元。我们构建了RIIβ亚基敲除小鼠，该小鼠健康且摄食正常，但却呈现明显的低脂消瘦表型，全身脂肪含量仅为正常值50%；此外，其脂肪组织褐变相关分子UCP-1表达升高，机体产热量与基础代谢率增加，提示其脂肪细胞褐变水平增强，并可能由此而获得低脂消瘦表型。我们确定了下丘脑GABA能神经元RIIβ亚基缺失是导致以上表型的原因，但机制不明。我们推测：下丘脑GABA能神经元PKA-RIIβ信号通路，可能是通过调控脂肪组织褐变，来实现对机体脂肪稳态的调节。本项目将研究PKA-RIIβ信号对脂肪组织褐变的调控机制，并利用我们新研发的基因工程酶学技术和转录子组学技术，阐明PKA调控褐变的神经与分子机理。该研究有助于深入认识脂肪代谢中枢调控的分子机理，有利于酶类为靶点的新药研究，为肥胖等代谢疾病的治疗提供新途径。

PKA, as a key factor in the cell signal transduction, plays critical roles in the regulation of homeostasis of lipid metabolism. PKA comprised of RIIβ subunit is distributed in brain and adipocytes. We created the RIIβ knockout mice. The mice are healthy and show lean phenotypes by 50% adiposity reduction comparing to wild type, and have normal food-intake. Additionally, the mice exhibit higher expression of UCP-1, a marker of browning of adipocytes, and elevated thermogenesis as well as raised basal metabolic rate, which suggest that RIIβ knockout mice have an enhanced browning level. We confirmed that the deficiency of RIIβ in hypothalamic GABAergic neurons confers these phenotypes; however, the mechanism is unknown. We hypothesize that PKA-RIIβ signaling in hypothalamic GABAergic neurons might be involved in the control of homeostasis of lipid metabolism by regulating the browning of adipocytes. In this project, we plan to study on the mechanism underlying PKA-RIIβ signaling in the hypothalamic GABAergic neurons regulates the browning of peripheral adipose tissues, with the help of our newly developed genetically engineered mutants for enzymatic study and transcriptome technology. This study will be helpful to understand the mechanism controlling the metabolism and advantageous to the new drug discovery targeted to enzyme, also will provide a new approach for the treatment of metabolic diseases and obesity.