AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation

作者全名：Qiu, Sheng; Wu, Qinan; Wang, Hao; Liu, Dongfang; Chen, Chen; Zhu, Zhiming; Zheng, Hongting; Yang, Gangyi; Li, Ling; Yang, Mengliu

作者地址：[Qiu, Sheng; Wang, Hao; Liu, Dongfang; Yang, Gangyi; Li, Ling; Yang, Mengliu] Chongqing Med Univ, Affiliated Hosp 2, Dept Endocrinol, Chongqing 400010, Peoples R China; [Qiu, Sheng; Li, Ling] Chongqing Med Univ, Dept Lab Med, Key Lab Med Diagnost, Minist Educ, Chongqing 400016, Peoples R China; [Wu, Qinan] Chongqing Med Univ, Affiliated Dazu Hosp, Dept Endocrinol, Chongqing 402360, Peoples R China; [Chen, Chen] Univ Queensland, Fac Med, Endocrinol, SBMS, Brisbane, Qld 4072, Australia; [Zhu, Zhiming] Third Mil Med Univ, Daping Hosp, Dept Hypertens & Endocrinol, Chongqing 400042, Peoples R China; [Zheng, Hongting] Third Mil Med Univ, Xinqiao Hosp, Dept Endocrinol, Chongqing 400037, Peoples R China

通信作者：Yang, GY; Li, L; Yang, ML (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Endocrinol, Chongqing 400010, Peoples R China.; Li, L (通讯作者)，Chongqing Med Univ, Dept Lab Med, Key Lab Med Diagnost, Minist Educ, Chongqing 400016, Peoples R China.

来源：NATURE COMMUNICATIONS

ESI学科分类：　

WOS号：WOS:001207631600003

JCR分区：Q1

影响因子：14.7

年份：2024

卷号：15

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要：Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons. The hypothalamus is essential for energy regulation, with POMC neurons crucial for controlling food intake and energy balance. Here, the authors show that AZGP1 improves leptin sensitivity in POMC neurons, aiding in weight loss and energy use by altering leptin-JAK2-STAT3 signalling.

基金机构：National Natural Science Foundation of China (National Science Foundation of China) [82170816, U22A20289, 82300922, 82270853, 82370852]; National Natural Science Foundation [2022MD713711]; China Postdoctoral Science Foundation [CSTB2022NSCQ-BHX0670]; Chongqing Natural Science Foundation Project-Postdoctoral Science Foundation Project [W0159]; CQMU Program for Youth Innovation in Future Medicine

基金资助正文：We thank Dr. Feifan Guo (Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China) and Dr. Chaohong Liu (Huazhong University of Science and Technology, Wuhan, China) for kindly providing us with the POMC-CreER mice, AI9 (tdTomato) reporter mice and Stat3 fl/fl mice. This work was supported by grants from the National Natural Science Foundation (82170816 and U22A20289 to L.L., 82300922 to S.Q., 82270853 to G.Y., and 82370852 to M.Y.), China Postdoctoral Science Foundation (2022MD713711 to S.Q.), Chongqing Natural Science Foundation Project-Postdoctoral Science Foundation Project (CSTB2022NSCQ-BHX0670 to S.Q.) and the CQMU Program for Youth Innovation in Future Medicine (W0159) to S.Q. and M.Y.