2031-P: Adipose-Specific Lack of Hexose-6-Phosphate Dehydrogenase Causes Inactivation of Adipose Glucocorticoids and Improves Metabolic Phenotype in Male Mice

Abstract

Excessive glucocorticoids (GCs) production in adipose tissue promotes the development of visceral obesity and the metabolic syndrome. 11β-Hydroxysteroid dehydrogenase type 1 (11 β-HSD1) is critical for controlling intracellular GC production in adipose tissue, and this process is also regulated by hexose-6-phosphate dehydrogenase (H6PDH) that provides cofactor NADPH for 11β-HSD1 amplifying local GC production. To better understand the integrated molecular and physiological role of adipose H6PDH, we created a tissue specific knockout of H6PDH gene mouse model in adipocytes (H6PDHAcKO mice) and characterized the metabolic related phenotypes. H6PDHAcKO mice had decreased levels of intra-adipose corticosterone with reduction of 11β-HSD1 activity in response to H6PDH deletion in adipose tissue. Moreover, H6PDHAcKO mice also exhibited reduced fasting blood glucose levels and increased glucose tolerance with increased insulin sensitivity. In addition, plasma FFA levels were decreased with a concomitant decrease in the expression of lipase ATGL and HSL in the abdominal adipose tissue. These results indicate that inactivation of H6PDH expression in adipose tissue is sufficient to cause intra-adipose GC inactivation leading to the favorable pattern of metabolic phenotype. These data suggest that H6PDHAcKO mice may provide a good model for study the potential contributions of fat-specific H6PDH inhibition in the metabolic phenotype and other pathological disorders in vivo. Disclosure J. Wang: None. X. Wang: None. K. Lutfy: None. T. Friedman: None. M. Jiang: None. Y. Liu: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (SC1DK104821)