title: An ATF4-ATG5 signaling in hypothalamic POMC neurons regulates obesity.
abstract: ATF4 (activating transcription factor 4) is an important transcription factor that has many biological functions, while its role in hypothalamic POMC (pro-opiomelanocortin-α) neurons in the regulation of energy homeostasis has not been explored. We recently discovered that mice with an Atf4 deletion specific to POMC neurons (PAKO mice) are lean and have higher energy expenditure. Furthermore, these mice are resistant to high-fat diet (HFD)-induced obesity and obesity-related metabolic disorders. Mechanistically, we found the expression of ATG5 (autophagy-related 5) is upregulated in POMC neurons of PAKO mice, and ATF4 regulates ATG5 expression by binding directly to its promoter. Mice with Atf4 and Atg5 double knockout in POMC neurons have reduced energy expenditure and gain more fat mass compared with PAKO mice under a HFD. Finally, the effect of Atf4 knockout in POMC neurons is possibly mediated by enhanced ATG5-dependent macroautophagy/autophagy and α-melanocyte-stimulating hormone (α-MSH) production in the hypothalamus. Together, this work not only identifies a beneficial role for ATF4 in hypothalamic POMC neurons in the regulation of obesity, but also provides a new potential therapeutic target for obesity and obesity-related metabolic diseases.
authors.affiliation: a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.
authors.forename: Yuzhong
authors.identifier: http://orcid.org/0000-0001-7660-8125
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.
authors.forename: Yalan
authors.initials: Y
authors.lastname: Deng
authors.affiliation: a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.
authors.forename: Feixiang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Xia
authors.affiliation: a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Li
authors.affiliation: a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.
authors.forename: Shanghai
authors.initials: S
authors.lastname: Chen
authors.affiliation: a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.
authors.forename: Zhixue
authors.identifier: http://orcid.org/0000-0001-7597-5337
authors.initials: Z
authors.lastname: Liu
authors.affiliation: a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ying
authors.affiliation: a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Zhai
authors.affiliation: a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.
authors.forename: Feifan
authors.identifier: http://orcid.org/0000-0001-6748-4546
authors.initials: F
authors.lastname: Guo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000071187:Autophagy-Related Protein 5; D051701:Activating Transcription Factor 4; D011333:Pro-Opiomelanocortin
keywords: ATF4; ATG5; POMC neurons; autophagy; obesity