title: ATF4/ATG5 Signaling in Hypothalamic Proopiomelanocortin Neurons Regulates Fat Mass via Affecting Energy Expenditure.
abstract: Although many biological functions of activating transcription factor 4 (ATF4) have been identified, a role of hypothalamic ATF4 in the regulation of energy homeostasis is poorly understood. In this study, we showed that hypothalamic proopiomelanocortin (POMC) neuron-specific ATF4 knockout (PAKO) mice are lean and have higher energy expenditure. Furthermore, PAKO mice were resistant to high-fat diet-induced obesity, glucose intolerance, and leptin resistance. Moreover, the expression of autophagy protein 5 (ATG5) was increased or decreased by ATF4 knockdown or overexpression, respectively, and ATF4 inhibited the transcription of ATG5 by binding to the basic zipper-containing protein sites on its promoter. Importantly, mice with double knockout of ATF4 and ATG5 in POMC neurons gained more fat mass and reduced energy expenditure compared with PAKO mice under a high-fat diet. Finally, the effect of ATF4 deletion in POMC neurons was possibly mediated via enhanced ATG5-dependent autophagy and α-melanocyte-stimulating hormone production in the hypothalamus. Taken together, these results identify the beneficial role of hypothalamic ATF4/ATG5 axis in the regulation of energy expenditure, obesity, and obesity-related metabolic disorders, which suggests that ATF4/ATG5 axis in the hypothalamus may be a new potential therapeutic target for treating obesity and obesity-related metabolic diseases.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes 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: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes 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: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes 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: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes 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: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes 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: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhixue
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes 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: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes 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: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes 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: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes 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: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China ffguo@sibs.ac.cn.
authors.forename: Feifan
authors.initials: F
authors.lastname: Guo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics* / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000473:pathology; D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000071187:Autophagy-Related Protein 5 / Q000235:genetics* / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D003345:Corticosterone / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D005951:Glucose Tolerance Test; D013006:Growth Hormone / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D009929:Organ Size; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C081452:Atf4 protein, mouse; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D051701:Activating Transcription Factor 4; D011333:Pro-Opiomelanocortin; D013006:Growth Hormone; D003345:Corticosterone; D009638:Norepinephrine