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- Title
SGK1/FOXO3 Signaling in Hypothalamic POMC Neurons Mediates Glucocorticoid-Increased Adiposity.
- Authors
Yalan Deng; Yuzhong Xiao; Feixiang Yuan; Yaping Liu; Xiaoxue Jiang; Jiali Deng; Fejes-Toth, Geza; Naray-Fejes-Toth, Aniko; Shanghai Chen; Yan Chen; Hao Ying; Qiwei Zhai; Yousheng Shu; Feifan Guo
- Abstract
Although the central nervous system has been implicated in glucocorticoid-induced gain of fat mass, the underlying mechanisms are poorly understood. The aim of this study was to investigate the possible involvement of hypothalamic serum- and glucocorticoid-regulated kinase 1 (SGK1) in glucocorticoid-increased adiposity. It is well known that SGK1 expression is induced by acute glucocorticoid treatment, but it is interesting that we found its expression to be decreased in the arcuate nucleus of the hypothalamus, including proopiomelanocortin (POMC) neurons, following chronic dexamethasone (Dex) treatment. To study the role of SGK1 in POMC neurons, we produced mice that developed or experienced adult-onset SGK1 deletion in POMC neurons (PSKO). As observed in Dex-treated mice, PSKO mice exhibited increased adiposity and decreased energy expenditure. Mice overexpressing constitutively active SGK1 in POMC neurons consistently had the opposite phenotype and did not experience Dex-increased adiposity. Finally, Dex decreased hypothalamic α-melanocyte-stimulating hormone (α-MSH) content and its precursor Pomc expression via SGK1/FOXO3 signaling, and intracerebroventricular injection of α-MSH or adenovirus-mediated FOXO3 knockdown in the arcuate nucleus largely reversed the metabolic alterations in PSKO mice. These results demonstrate that POMC SGK1/FOXO3 signaling mediates glucocorticoid-increased adiposity, providing new insights into the mechanistic link between glucocorticoids and fat accumulation and important hints for possible treatment targets for obesity.
- Subjects
PROTEIN metabolism; ADIPOSE tissues; ANIMAL experimentation; HUMAN body composition; COMPARATIVE studies; ENERGY metabolism; GLUCOCORTICOIDS; HYPOTHALAMUS; RESEARCH methodology; MEDICAL cooperation; MICE; NEURONS; PROTEIN precursors; PROTEINS; RESEARCH; TRANSFERASES; EVALUATION research; DEXAMETHASONE; PHARMACODYNAMICS
- Publication
Diabetes, 2018, Vol 67, Issue 4, p569
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db17-1069