mTORC1 信号通路在脂肪组织米色化和机体能量代谢调控中的作用和机制研究

脂肪组织功能的紊乱与肥胖和糖尿病等代谢性疾病的发生密切相关, 但其机制仍待进一步阐明。最近的研究发现在冷刺激或者β-肾上腺素受体激活可诱导白色脂肪组织UCP1的高表达，即米色化。我们的前期研究发现脂肪组织特异性敲除mTORC1上游的直接正调控分子Rheb基因不仅可以对抗高脂饮食诱导的肥胖，而且明显降低了动物的血糖水平和改善了胰岛素敏感性，同时还出现皮下脂肪组织明显增加的UCP1的表达。我们推测mTORC1信号通路可能是白色脂肪组织米色化的关键负调控因子，而脂肪组织特异性地阻断mTORC1信号通路可能通过促进脂肪组织米色化而增加能量的消耗，降低肥胖。在本项目中将继续利用脂肪组织特异性的Rheb敲除小鼠模型以及mTORC1信号通路改变的细胞模型来研究mTORC1信号通路在白色脂肪组织米色化及产热中的作用、相关信号途径和分子机制。为肥胖和糖尿病等代谢性疾病的预防和治疗提供新的理论基楚。

Adipose tissue dysfunction is closely associated to obesity and diabetes, yet the underlying mechanisms remain to be elucidated. Recent studies have discovered that cold stress or β- adrenergic receptor activation could induce uncoupling protein 1 (UCP1) expression in white adipose tissue (WAT), a phenomena called "beigeing" or "browning". Our preliminary data showed that fat-specific knockout of ras homologue enriched in brain (Rheb), a positive regulator of mammalian target of rapamycin (mTOR), substantially reduced adipose tissue mass, protected mice against high fat diet-induced obesity, suppressed blood glucose levels, and improved insulin sensitivity in mice. More importantly, the fat-specific Rheb knockout mice displayed enhanced expression levels of UCP1 in subcutaneous WAT. We hypothesize that the mTOR complex 1 (mTORC1) signaling pathway might play a negative role in the beigeing process of WAT, and fat-specific disruption of mTORC1 signaling could protect against obesity and improve insulin sensitivity by promoting the beigeing process in WAT. In the proposed studies, through fat-specific knockout Rheb mice as well as mTORC1 signaling disrupted cellular models, we will investigate the functional roles of mTORC1 in the beigeing process of WAT and the underlying mechanisms. The successful completion of the studies will uncover novel targets for the prevention and treatment of obesity-related diseases.