Scientists Reveal New Mechanism of Central Nervous System Regulated Glucocorticoid-induced Obesity
The name glucocorticoid (glucose + cortex + steroid) is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure. It is essential for life, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions.
Various synthetic glucocorticoids are available. These are widely utilized in general medical practice and numerous specialties either as replacement therapy in glucocorticoid deficiency or to suppress the immune system, and also effective anti-inflammatory, anti-shock drug. In addition to the overwhelming beneficial effects of glucocorticoid, chronic glucocorticoid treatment is shown to cause numerous adverse metabolic outcomes, including fat mass gain, however the underlying mechanisms are poorly understood.
Hypothalamus is an integral part of the brain, which regulates the internal organs and endocrine system. Specific populations of neurons in the arcuate nucleus (ARC) of hypothalamus include neurons coexpressing orexigenic neuropeptides agouti-related protein (AgRP) and neuropeptide Y (NPY) along with neurons coexpressing anorexigenic pro-opiomelanocortin (POMC) precursor and cocaine and amphetamine-related transcript (CART), extensively involved in the regulation of appetite, body weight and metabolism.
POMC is a protein expressed and secreted from POMC neurons and cleaved by prohormone convertases to produce α-melanocyte stimulating hormone (α-MSH). α-MSH functions as a key hub linking the CNS to peripheral organs through the sympathetic nervous system (SNS). The study on the role of POMC neurons in glucocorticoid-induced obesity will provide important theoretical basis on the pathogenesis and treatment of obesity.
On January 10, 2018, the international academic journal Diabetes online published the research article of Dr. GUO Feifan’s group of Key Laboratory of Nutrition Metabolism and Food Safety of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences: “SGK1/FOXO3 signaling in hypothalamic POMC neurons mediates glucocorticoid-increased adiposity”. The research found that SGK1 expression was decreased in the arcuate nucleus of the hypothalamus, including POMC neurons, following chronic dexamethasone (Dex) treatment, and mice overexpressing constitutively active SGK1 in POMC neurons (PSOE) prevented from Dex-increased adiposity. The research provides a theoretical basis and new ideas on the pathogenesis and treatment of obesity.
Under the guidance of the Principal Investigator Dr. GUO Feifan, PHD student DENG Yalan and other researchers demonstrated that acute Dex treatment induces SGK1. Interestingly, the group found that SGK1 expression was decreased in ARC POMC neurons of chronic Dex-treated mice. The difference in SGK1 expression under acute or chronic Dex treatment may be caused by differences in glucocorticoid receptor (GR) activity under different conditions.
To study a role of SGK1 in POMC neurons, mice with development or adult-onset SGK1 deletion in POMC neurons (PSKO) were then produced. As observed in Dex-treated mice, PSKO mice exhibited increased adiposity and decreased energy expenditure. Consistently, PSOE mice had the opposite phenotype and prevented from Dex-increased adiposity. Finally, Dex decreased hypothalamic α-MSH content and its precursor Pomc expression via SGK1/Forkhead box O3 (FOXO3) signaling and intracerebroventricular injection of α-MSH or adenovirus-mediated FOXO3 knockdown in ARC largely reversed the metabolic alterations in PSKO mice.
These results demonstrate that POMC SGK1/FOXO3 signaling mediates glucocorticoid-increased adiposity, providing new insights into mechanistic link between glucocorticoid and fat accumulation and important hints for possible treatment targets for obesity.
This study was supported by Professor SHU Yousheng of Beijing Normal University (the co-corresponding author of the paper), the Principal Investigators Dr. CHEN Yan, Dr. ZHAI Qiwei and Dr. YING Hao from Shanghai Institutes for Biological Sciences. This study was funded by the National Natural Science Foundation of China, Shanghai Science and Technology Commission and Chinese Academy of Sciences.
Figure: SGK1/FOXO3 signaling in hypothalamic POMC neurons mediates glucocorticoid-increased adiposity (Image by Dr.GUO Feifan’s lab)