POMC神经元除抑制食欲外还可通过调控脂肪产热抵抗肥胖。我们前期研究证实IRE1α在POMC神经元调控外周脂肪产热过程中具有重要作用，但其上游调控机制尚未明确。进一步研究发现，通过高脂饮食诱导小鼠POMC神经元HIF2α表达下调，外周脂肪产热减少；而过表达HIF2α，不但能抵抗饮食诱导的肥胖，还可增强外周脂肪产热。初步证实HIF2α是ABL1的上游调控因子，且ABL1具有活化IRE1α和促进其蛋白表达的作用。据此我们提出高脂诱导POMC神经元HIF2α下调，抑制ABL1对IRE1α的活化及表达，减少外周脂肪产热的科学假说。本项目拟用POMC神经元HIF2α过表达/敲除小鼠，探讨：①高脂饮食如何调控POMC神经元HIF2α的表达；②HIF2α对POMC神经元的分子调控机制；③HIF2α/ABL1/IRE1α信号通路如何调控POMC神经元并对脂肪产热的作用及机制，探索中枢调控代谢的新靶点。

In addition to suppressing appetite, POMC neurons could prohibit the obesity through the regulation of the adipocyte thermogenesis. Our previous studies have confirmed that IRE1α plays a pivotal role in the regulation of the thermogenesis od adipose tissue in POMC neurons, while the systemic regulatory mechanism remains unknown. Our preliminary investigation has demonstrated that high fat diet-induced obesity is followed with the downregulation of HIF2α expression in POMC neurons and the reduction of peripheral thermogenesis. POMC neuron-specific overexpression of HIF2α is resistance to the high fat diet-induced weight-gain and induce the thermogenesis. Further investigation indicated that HIF2α directly upregulates ALB1 expression, who activation could directly activate IRE1α expression and increase its protein level in POMC neurons. Based the preliminary data, we hypothesized that HIF2α as an essential transcription factor in POMC neurons is directly involved in regulating the ALB1-IRE1α pathway with respect to the high fat diet-induced obesity and peripheral thermogenesis. In order prove the hypothesis, we sought the take advantage of the POMC neuron-specific knockout and overexpression mice to further dissect the functional importance and mechanistic aspect of HIF2α in POMC neurons to regulate the target pathways and the peripheral thermogenesis: ① How does high fat diet regulate HIF2α expression in POMC neurons; ② Understand the regulatory mechanism of HIF2α in POMC neurons; ③ Determine the molecular mechanism of the HIF2α-ABL1-IRE1α pathway in POMC neurons regarding the thermogenesis of the adipose tissue. By addressing following question will help us further understand and identify the new therapeutic target of the central nerve system-mediated metabolic regulation.