Deletion of ATF4 in AgRP Neurons Promotes Fat Loss Mainly via Increasing Energy Expenditure

• DOI: 10.2337/db16-0954
• Publication Date: 2016-12-20T02:06:08Z
• Authors: Jiali Deng; Feixiang Yuan; Yajie Guo; Yuzhong Xiao; Yuguo Niu; Yalan Deng; Xiao Han; Youfei Guan; Shanghai Chen; Feifan Guo
• Keywords: ATF4; Energy homeostasis; FOXO1; Steatosis

Although many functions of activating transcription factor 4 (ATF4) are identified, a role ATF4 in the hypothalamus regulating energy homeostasis is unknown. Here, we generated adult-onset agouti-related peptide neuron–specific knockout (AgRP-ATF4 KO) mice and found that these were lean, with improved insulin leptin sensitivity decreased hepatic lipid accumulation. Furthermore, AgRP-ATF4 KO showed reduced food intake increased expenditure, mainly because enhanced thermogenesis brown adipose tissue. Moreover, resistant to high-fat diet–induced obesity, resistance, liver steatosis maintained at higher body temperature under cold stress. Interestingly, expression FOXO1 was directly regulated by via binding cAMP-responsive element site on its promoter hypothalamic GT1-7 cells. Finally, Foxo1 arcuate nucleus (ARC) mice, adenovirus-mediated overexpression ARC fat mass mice. Collectively, our data demonstrate novel function AgRP neurons balance metabolism suggest as potential drug target for treating obesity related metabolic disorders.