Inhibition of Hexose-6-Phosphate Dehydrogenase Expression in Subcutaneous Adipose Tissue Ameliorates Glucocorticoid - Induced Local Lipogenesis and Insulin Resistance in Male Mice

Presentation Number: SUN 608
Date of Presentation: April 2nd, 2017

Fubing Wang1, Carl Sims1, Desean L. Lee2, Ying Wang1, Adaku Ume1, Kabirullah Lutfy3, Amiya P Sinha-Hikim2, Theodore C Friedman4 and Yan Jun Liu*1
1Charles R. Drew University of Medicine and Science, Los Angeles, CA, 2Charles R Drew University of Medicine and Science, Los Angeles, CA, 3Western University of Medicine and Science, 4Charles R. Drew Univeristy of Medicine and Science, Los Angeles, CA

Abstract

Glucocorticoid receptor (GR) antagonists can block the adverse adiposity and other metabolic consequences associated with circulating glucocorticoid (GC) excess. Tissue specific sensitivity to circulating GCs is controlled by intracellular GR and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which is regulated by hexose-6-phosphate dehydrogenase (H6PDH). Here, we explored whether tissue-specific modulation of H6PDH in subcutaneous adipose tissue would play a functional role in hypercortisolemia-associated fat adiposity and insulin sensitivity. To address this research question, we examined the effects of GR antagonist mifepristone on lipogenic genes and insulin signaling in subcutaneous adipose of C57BL/6J mice exposed to excess GCs. Corticosteroids exposure increased abdominal subcutaneous fat mass and activated adipogenic signals of glycogen synthase kinase (GSK3β) with impairment of pThr308 Akt and corresponding up-regulation of 11ß-HSD1 and H6PDH expression in subcutaneous fat depots. Conversely, mifepristone treatment reduced GC-induced activation of pSer9 GSK3β, reduced de novo lipogenic gene expression (ACC, ACL and PEPCK) and reduced local fat adiposity and weight gain induced by excess GC exposure. Suppression of pSer9 GSK3β by mifepristone was accompanied by activation of pThr308 Akt with a concomitant reduction of H6PDH expression within adipose tissue in mice treated with excess GCs. In addition, mifepristone attenuated GC-induced decrease in GLUT1 and GLUT4 with activation of IR and IRS1 gene expression. These findings suggest that the GR antagonist mifepristone exerts some of its metabolic benefits on hypercortisolism-induced adiposity and insulin resistance, at least in part, through the suppression of subcutaneous adipose H6PDH and 11ß-HSD1.

 

Nothing to Disclose: FW, CS, DLL, YW, AU, KL, APS, TCF, YJL