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- Title
Deletion of ATF4 in AgRP Neurons Promotes Fat Loss Mainly via Increasing Energy Expenditure.
- Authors
Jiali Deng; Feixiang Yuan; Yajie Guo; Yuzhong Xiao; Yuguo Niu; Yalan Deng; Xiao Han; Youfei Guan; Shanghai Chen; Feifan Guo; Deng, Jiali; Yuan, Feixiang; Guo, Yajie; Xiao, Yuzhong; Niu, Yuguo; Deng, Yalan; Han, Xiao; Guan, Youfei; Chen, Shanghai; Guo, Feifan
- Abstract
Although many functions of activating transcription factor 4 (ATF4) are identified, a role of ATF4 in the hypothalamus in regulating energy homeostasis is unknown. Here, we generated adult-onset agouti-related peptide neuron-specific ATF4 knockout (AgRP-ATF4 KO) mice and found that these mice were lean, with improved insulin and leptin sensitivity and decreased hepatic lipid accumulation. Furthermore, AgRP-ATF4 KO mice showed reduced food intake and increased energy expenditure, mainly because of enhanced thermogenesis in brown adipose tissue. Moreover, AgRP-ATF4 KO mice were resistant to high-fat diet-induced obesity, insulin resistance, and liver steatosis and maintained at a higher body temperature under cold stress. Interestingly, the expression of FOXO1 was directly regulated by ATF4 via binding to the cAMP-responsive element site on its promoter in hypothalamic GT1-7 cells. Finally, Foxo1 expression was reduced in the arcuate nucleus (ARC) of the hypothalamus of AgRP-ATF4 KO mice, and adenovirus-mediated overexpression of FOXO1 in ARC increased the fat mass in AgRP-ATF4 KO mice. Collectively, our data demonstrate a novel function of ATF4 in AgRP neurons of the hypothalamus in energy balance and lipid metabolism and suggest hypothalamic ATF4 as a potential drug target for treating obesity and its related metabolic disorders.
- Subjects
TRANSCRIPTION factors; HOMEOSTASIS; PEPTIDES; NEURONS; LIPIDS; ANIMAL models in research; ANIMAL experimentation; DIET; ENERGY metabolism; GENETIC disorders; GROWTH factors; HYPOTHALAMUS; INGESTION; INSULIN; INSULIN resistance; LIPID metabolism disorders; LIVER; MICE; OBESITY; PROTEINS; LEPTIN
- Publication
Diabetes, 2017, Vol 66, Issue 3, p640
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db16-0954