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. Here, we showed that hypothalamic pro-opiomelanocortin (POMC) neurons specific ATF4 knockout (PAKO) mice are lean and have higher energy expenditure. Furthermore, PAKO mice were resistant to high-fat diet (HFD)-induced obesity, glucose intolerance and leptin resistance. Moreover, the expression of autophagy protein 5 (ATG5) was increased or decreased by ATF4 knockdown or over-expression, respectively, and ATF4 inhibited the transcription of ATG5 by binding to the basic zipper-containing protein (bZIP) sites on its promoter. Importantly, mice with double knockout of ATF4 and ATG5 in POMC neurons (DKO) gained more fat mass and reduced energy expenditure compared with PAKO mice under a HFD. Finally, the effect of ATF4 deletion in POMC neurons was possibly mediated via enhanced ATG5-dependent autophagy and α-melanocyte-stimulating hormone (α-MSH) 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 maybe a new potential therapeutic target for treating obesity and obesity-related metabolic diseases.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-1546/-/DC1.
- Received December 15, 2016.
- Accepted February 12, 2017.
- © 2017 by the American Diabetes Association.