期刊
DIABETES
卷 66, 期 3, 页码 640-650出版社
AMER DIABETES ASSOC
DOI: 10.2337/db16-0954
关键词
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资金
- National Natural Science Foundation [81130076, 81325005, 31271269, 81300659, 81400792, 81471076, 81570777, 81500622, 81390350]
- Shanghai Science and Technology Commission [16JC1404900]
- International S&T Cooperation Program of China (Singapore) [2014DFG32470]
- international Partnership Program For Creative Research Teams (CAS/SAFEA)
- One Hundred Talents Program of the Chinese Academy of Sciences
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.
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