Increased glycogen synthase kinase-3β and hexose-6-phosphate dehydrogenase expression in adipose tissue may contribute to glucocorticoid-induced mouse visceral adiposity

• Published in: International Journal of Obesity 2016-08, Vol.40 (8), p.1233-1241
• Main Authors: Yan, C, Yang, H, Wang, Y, Dong, Y, Yu, F, Wu, Y, Wang, W, Adaku, U, Lutfy, K, Friedman, T C, Tian, S, Liu, Y
• Format: Article
• Language: English
• Subjects: 38; 631/443; 631/443/319/1642/393; 631/45/607/1168; 631/45/607/275; 631/92/436/108; 64; Accumulation; Acetyl-CoA carboxylase; Adipocytes; Adipocytes - enzymology; Adipocytes - metabolism; Adipogenesis - drug effects; Adipose tissue; Adipose Tissue - enzymology; Adipose tissues; Adiposity - drug effects; Adiposity - genetics; AKT protein; Animal tissues; Animals; ATP citrate lyase; Attenuation; Body fat; Carbohydrate Dehydrogenases - biosynthesis; Carbohydrate Dehydrogenases - metabolism; Corticoids; Corticosteroids; Corticosterone; Cushing syndrome; Dehydrogenase; Dehydrogenases; Disease Models, Animal; Enzymes; Epidemiology; Gene expression; Glucocorticoids; Glucocorticoids - pharmacology; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - biosynthesis; Glycogen Synthase Kinase 3 beta - metabolism; Glycogens; Health Promotion and Disease Prevention; Hexose; Hormone Antagonists - pharmacology; Hydroxysteroids; Internal Medicine; Intra-Abdominal Fat - drug effects; Kinases; Lipids; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Inbred C57BL; Mifepristone; Mifepristone - pharmacology; Obesity; Obesity, Abdominal - enzymology; Obesity, Abdominal - genetics; Obesity, Abdominal - metabolism; original-article; Peroxisome proliferator-activated receptors; Phenotypes; Phosphorylation; Physiological aspects; Public Health; Receptors, Glucocorticoid - antagonists & inhibitors; Reduction; Transcription
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2016.57

Background: Increased adiposity in visceral depots is a crucial feature associated with glucocorticoid (GC) excess. The action of GCs in a target tissue is regulated by GC receptor (GR) and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) coupled with hexose-6-phosphate dehydrogenase (H6pdh). Glycogen synthase kinase-3β (GSK3β) is known to be a crucial mediator of ligand-dependent gene transcription. We hypothesized that the major effects of corticosteroids on adipose fat accumulation are in part mediated by changes in GSK3β and H6pdh. Methods: We characterized the alterations of GSK3β and GC metabolic enzymes, and determined the impact of GR antagonist mifepristone on obesity-related genes and the expression of H6pdh and 11ß-HSD1 in adipose tissue of mice exposed to excess GC as well as in in vitro studies using 3T3-L1 adipocytes treated with GCs. Results: Corticosterone (CORT) exposure increased abdominal fat mass and induced expression of lipid synthase acetyl-CoA carboxylase and ATP-citrate lyase with activation of GSK3β phosphorylation in abdominal adipose tissue of C57BL/6J mice. Increased pSer 9 GSK3β was correlated with the induction of H6pdh and 11ß-HSD1. In addition, mifepristone treatment reversed the production of H6pdh and attenuated CORT-mediated production of 11ß-HSD1 and lipogenic gene expression with reduction of pSer 9 GSK3β, thereby leading to improvement of phenotype of adiposity within adipose tissue in mice treated with excess GCs. Suppression of pSer 9 GSK3β by mifepristone was accompanied by activation of pThr 308 Akt and blockade of CORT-induced adipogenic transcriptor C/EBPα and PPARγ. In addition, mifepristone also attenuated CORT-mediated activation of IRE1α/XBP1. In addition, reduction of H6pdh by shRNA showed comparable effects to mifepristone on attenuating CORT-induced expression of GC metabolic enzymes and improved lipid accumulation in vitro in 3T3-L1 adipocytes. Conclusion: These findings suggest that elevated adipose GSK3β and H6pdh expression contribute to 11ß-HSD1 mediating hypercortisolism associated with visceral adiposity.