脑神经网络调控白色脂肪米色化与能量代谢稳态的机制研究

Neural networks centrally control the metabolic homeostasis. We found that PKA-RIIβ signaling in hypothalamic GABAergic neurons regulates the lipid metabolism. We created the RIIβ knockout mice, the mice are lean by 50% adiposity reduction, resistant to high-fat-food induced obesity and fatty liver, resistant to type II diabetes, and have longer life span. We found that the deficiency of PKA-RIIβ subunit in hypothalamic GABAergic neural network confers these phenotypes; however, the molecular and neural mechanisms are unknown. Recently, we further found that the mice exhibit elevated expressions of adipocytic beige markers, which contribute to the raised thermogenesis and basal metabolic rate, indicating the hypothalamic PKA signaling is involved in the regulation of the beigeing of white adipose tissue. Notably, the high levels of beigeing promoted by neural signals were observed in mice and human, which contribute to the healthy metabolic phenotypes. Therefore, based on the PKA signaling in hypothalamic neural networks, we plan to decipher the molecular and neural mechanism underlying the beigeing of white adipose tissue, utilizing our newly developed genetically engineered mutants for enzymatic study and translatomic technology, in conjunction with nerve tracing, optogenetics, pharmacogenetics, and translational medicine. This study will be helpful to understand the mechanism controlling the lipid metabolism and advantageous to the new drug discovery targeted to enzyme, it also will provide a new approach for the treatment of metabolic diseases and obesity.

脑神经网络调控能量代谢稳态。我们发现，下丘脑GABA能神经元PKA-RIIβ信号参与脂类代谢中枢调控。我们构建了PKA-RIIβ亚基敲除小鼠，其表型为：低脂（总脂肪为正常值50%）、抗击高脂饮食性肥胖、抵抗二型糖尿病、抵抗脂肪肝、及寿命延长等；而下丘脑GABA能神经元RIIβ缺失导致以上表型，但神经通路与分子机制不明。最近，我们进一步发现：该小鼠白色脂肪米色化因子表达激增、基础代谢率与产热量增加，提示下丘脑GABA能神经元PKA信号参与脂肪米色化调控；而且，神经源性脂肪米色化，存在于小鼠与人类，可能是健康代谢表型关键机制之一。本项目将以PKA-RIIβ信号为线索、解析下丘脑神经元网络、利用我们新研发的基因工程酶学技术与特异翻译组学技术、结合神经示踪、化学遗传等技术、兼顾转化医学研究策略，共同阐明白色脂肪米色化的神经与分子机理，并尝试酶类靶点新药研发、为肥胖等代谢疾病防治提供新途径。

本项目的研究背景：脑神经网络调控能量代谢稳态；我们前期工作发现，下丘脑GABA能神经元PKA-RIIβ信号参与脂类代谢中枢调控；我们构建了PKA-RIIβ亚基敲除小鼠，其表型为：低脂（总脂肪为正常值50%）、抗击高脂饮食性肥胖、抵抗二型糖尿病、抵抗脂肪肝、及寿命延长等；而下丘脑GABA能神经元RIIβ缺失导致以上表型，但神经通路与分子机制不明。主要研究内容：我们发现该小鼠白色脂肪米色化因子表达激增、基础代谢率与产热量增加，因此，本项目聚焦研究下丘脑GABA能神经元PKA信号参与脂肪米色化调控机制。重要结果及关键数据：我们在本研究中发现：下丘脑背内侧核γ-氨基丁酸（GABA）能神经元RIIβ-PKA信号对脂肪组织褐变的调控机制，揭示了PKA发挥脂代谢稳态调控作用的特异脑神经结构与相关分子组学机理，明确了下丘脑背内侧核GABA能神经元PKA活性降低、及其所引起的GABA能神经元活性增强，是白色脂肪组织褐变的重要驱动因素。本研究的科学意义在于丰富了PKA调控脂代谢稳态的中枢神经机制，为肥胖的预防和治疗提供了新参考。