SAT-591 Lack of Adipose-Specific Hexose-6-Phosphate Dehydrogenase Improves Fat Metabolic Phenotype and Increases Insulin Sensitivity in Mice

Lack of adipose-specific hexose-6-phosphate dehydrogenase improves fat metabolic phenotype and increases insulin sensitivity in mice. ABSTRACT Increased glucocorticoids (GCs) production in adipose tissue promotes the development of visceral obesity and the MS. The action of GCs in adipose tissue is tightly regulated by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) coupled with hexose-6-phosphate dehydrogenase (H6PDH). However, the phenotypic consequences of reduction of fat-specific GC action caused by inactivation of H6PDH specifically in adipose tissue have not been explored. To better understand the physiological effects of adipose H6PDH, we generated a tissue-specific animal model of adipocyte-specific H6PDH deletion under the control of the murine adipocyte-specific adiponectin promoter (H6PDH(AcKO) mice). H6PDH(AcKO) mice exhibited complete absence of H6PDH expression and decreased GC production with reduction of 11β-HSD1 in adipose tissue. These mice had decreased abdominal fat mass with decreased adipose lipogenic gene expression associated with reduction of their transcription factor C/EBPs mRNA levels. Moreover, H6PDH(AcKO) mice also decreased adipose lipolysis and reduced plasma FFA levels. In addition, H6PDH(AcKO) mice decreased fasting glucose levels and increase tolerance to glucose and insulin. These data suggest that H6PDH(AcKO) mice may provide a good model for study the potential contribution of fat-specific H6PDH inhibition to improve the metabolic phenotype in vivo.