title: Transgenic overexpression of hexose-6-phosphate dehydrogenase in adipose tissue causes local glucocorticoid amplification and lipolysis in male mice.
abstract: The prereceptor activation of glucocorticoid production in adipose tissue by NADPH-dependent 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has emerged as a potential mechanism in the pathogenesis of visceral obesity and metabolic syndrome. Hexose-6-phosphate dehydrogenase (H6PDH) is an endoplasmic reticulum lumen-resident enzyme that generates cofactor NADPH and thus mediates 11β-HSD1 activity. To determine the role of adipose H6PDH in the prereceptor modulation of 11β-HSD1 and metabolic phenotypes, we generated a transgenic (Tg) mouse model overexpressing H6PDH under the control of the enhancer-promoter region of the adipocyte fatty acid-binding protein (aP2) gene (aP2/H6PDH Tg mice). Transgenic aP2/H6PDH mice exhibited relatively high expression of H6PDH and elevated corticosterone production with induction of 11β-HSD1 activity in adipose tissue. This increase in corticosterone production in aP2-H6PDH Tg mice resulted in mild abdominal fat accumulation with induction of C/EBP mRNA expression and slight weight gain. Transgenic aP2/H6PDH mice also exhibited fasting hyperglycemia and glucose intolerance with insulin resistance. In addition, the aP2/H6PDH Tg mice have elevated circulating free fatty acid levels with a concomitant increased adipose lipolytic action associated with elevated HSL mRNA and Ser(660) HSL phosphorylation within abdominal fat. These results suggest that increased H6PDH expression specifically in adipose tissue is sufficient to cause intra-adipose glucocorticoid production and adverse metabolic phenotypes. These findings suggest that the aP2/H6PDH Tg mice may provide a favorable model for studying the potential impact of H6PDH in the pathogenesis of human metabolic syndrome.
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, David Geffen School of Medicine at University of California Los Angeles, California;
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Limei
authors.initials: L
authors.lastname: Liu
authors.forename: Hanze
authors.initials: H
authors.lastname: Du
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nagaoka
authors.forename: Winnie
authors.initials: W
authors.lastname: Fan
authors.forename: Kabirullah
authors.initials: K
authors.lastname: Lutfy
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Friedman
authors.forename: Meisheng
authors.initials: M
authors.lastname: Jiang
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D050154:Adiposity; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005938:Glucocorticoids / Q000096:biosynthesis*; D007333:Insulin Resistance; D008066:Lipolysis / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D050556:Fatty Acid-Binding Proteins; D005230:Fatty Acids, Nonesterified; D005938:Glucocorticoids; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase
keywords: 11β-hydroxysteroid dehydrogenase type 1; transgenic mouse