FGF21介导棕色脂肪与白色脂肪之间对话调控机体能量代谢机制的研究

Obesity, which represents a major risk factor for a cluster of cardio-metabolic diseases, is caused by the positive energy balance. While white adipocytes serve to store excess energy, brown adipocytes facilitate energy expenditure by converting ATP production to heat dissipation . Besides classical brown adipocytes which are constitutively active and anatomically clustered in specific adipose depots, another inducible type of brown adipocytes-like cells (beige cells) are scattered within white adipose tissue (WAT). A growing body of evidence suggests that enhancing the activity or biogenesis of these two types of brown adipocytes represent a promising therapeutic strategy for obesity and its related medical complications. However, the precise mechanisms that control adaptive thermogenesis in these types of brown adipocytes remain poorly understood..Our recent studies in UCP1-null mice have uncovered a novel thermogenic program in subcutaneous WAT (scWAT) which is controlled by classical brown adipose tissue (cBAT). We found that UCP1-null mice do not have obese phenotype and paradoxically exhibit less adiposity after prolonged feeding with high fat diet (HFD), primarily due to the compensatory elevation of UCP1-independent energy expenditure in scWAT. These changes in UCP1-null mice are associated with obvious increases in mitochondrial number and activity in scWAT, although the structure and function of mitochondrion in cBAT are obviously impaired. Furthermore, we have identified a number of circulating factors in UCP1-null mice with potential activities to enhance thermogenesis in scWAT. Based on our preliminary data, we propose the existence of a novel cBAT-scWAT regulatory loop controlling thermogenesis and energy expenditure. Ablation of UCP1 causes mitochondrial stress responses in cBAT, leading to the secretion of FGF21 which travels to scWAT and induces UCP1-1 independent energy expenditure to compensate for dysfunctional BAT. To test this hypothesis, we will employ both in vivo and in vitro approaches todetermine whether FGF21 is a cBAT-derived factor mediating the crosstalk between cBAT and scWAT, to elucidate the molecular events on how FGF21 is induced in cBAT in response to UCP1 depletion and exert thermogenic functions in scWAT. The findings will not only enrich our understanding on biology of brown adipocytes and thermogenesis, but also provide knowledge base for future development of anti-obese therapies by targeting novel thermogenic pathways.

长期的能量摄入大于消耗导致肥胖，从而诱发一系列心血管代谢疾病。棕色脂肪(BAT)依赖线粒体内膜特有的解偶联蛋白-1(UCP-1)及丰富的线粒体将能量从生成ATP转化至产热效应。我们发现高脂饮食喂养的UCP-1剔除小鼠不仅没有肥胖反而拥有更低的体脂含量，得益于皮下白色脂肪(scWAT)中的代偿性非UCP-1依赖性的能量消耗，以及具备增强scWAT产热效应的循环因子如FGF21的水平升高。因此我们假设BAT-scWAT轴对话参与调控机体能量代谢，剔除UCP-1引起BAT内线粒体应激反应释放抵抗信号分子FGF21，介导scWAT启动代偿性非UCP-1依赖的能量消耗。为验证该假说，本课题将运用体内及体外研究策略去探究BAT产生的FGF21如何介导BAT与scWAT之间的对话并增强scWAT中非UCP-1依赖生热效应的分子机制，为针对BAT-WAT轴治疗肥胖提供新的治疗靶向。

长期的能量摄入大于消耗导致肥胖，从而诱发一系列心血管代谢疾病。棕色脂肪(BAT)依赖线粒体内膜特有的解偶联蛋白-1(UCP-1)及丰富的线粒体将能量从生成ATP转化至产热效应。我们发现高脂饮食喂养的UCP-1剔除小鼠不仅没有肥胖反而拥有更低的体脂含量，得益于皮下白色脂肪(scWAT)中的代偿性非UCP-1依赖性的能量消耗，以及具备增强scWAT产热效应的循环因子如FGF21的水平升高。因此我们假设BAT-scWAT轴对话参与调控机体能量代谢，剔除UCP-1引起BAT内线粒体应激反应释放抵抗信号分子FGF21，介导scWAT启动代偿性非UCP-1依赖的能量消耗。为验证该假说，本课题运用了体内及体外研究策略去探究BAT产生的FGF21如何介导BAT与scWAT之间的对话并增强scWAT中非UCP-1依赖生热效应的分子机制。 研究发现机体内存在BAT-WAT 轴通过对话交流来调控能量代谢，面对生热刺激BAT因UCP1的缺失引起线粒体应激反应，导致BAT衍生的循环因子水平改变如FGF21 或其它脂肪因子或代谢物，以内分泌方式作用触发scWAT 内信号通路，增强beige 脂肪细胞重塑以非UCP-1 依赖的其他替代方式消耗能量。UCP-1KO iWAT中 II型碘甲状腺素脱碘酶（Dio2）的表达水平和细胞内T3水平较WT iWAT 显著升高。为进一步深入了解T3调节的热生成，我们将甲状腺功能减退和甲状腺功能亢进小鼠的iWAT进行RNA测序。通过RNA序列数据的途径富集分析和经过以下验证，UCP-1 缺失的iWAT中T3和冷刺激可显著上调钠钾泵和通道T在mRNA和蛋白表达水平。在体外，T3处理可激活白色脂肪细胞中的Atp1a1和Atp1a2并增加耗氧量。T3诱发的氧气消耗可被ATP依赖性钠钾的药理抑制作用显著阻断，表明甲状腺激素通过加速与离子运输有关的能量消耗ATP。另一方面，T3诱导的Atp1a1和Atp1a2表达为组织特异性，需要甲状腺激素受体（TRs）和/或碳水化合物反应元件结合蛋白（ChREBP）。在白色脂肪细胞中，T3增强表达钠钾泵和离子泄漏通道的建立，建立了无效的阳离子传输循环产生热量。本研究强调了除经典的交感神经系统（SNS/UCP1）相关生热途径，甲状腺激素还可经非UCP-1依赖性途径诱导适应性产热，为治疗肥胖提供新的治疗靶向。