title: Susceptibility to diet-induced hepatic steatosis and glucocorticoid resistance in FK506-binding protein 52-deficient mice.
abstract: Although FK506-binding protein 52 (FKBP52) is an established positive regulator of glucocorticoid receptor (GR) activity, an in vivo role for FKBP52 in glucocorticoid control of metabolism has not been reported. To address this question, FKBP52(+/-) mice were placed on a high-fat (HF) diet known to induce obesity, hepatic steatosis, and insulin resistance. Tissue profiling of wild-type mice showed high levels of FKBP52 in the liver but little to no expression in muscle or adipose tissue, predicting a restricted pattern of FKBP52 effects on metabolism. In response to HF, FKBP52(+/-) mice demonstrated a susceptibility to hyperglycemia and hyperinsulinemia that correlated with reduced insulin clearance and reduced expression of hepatic CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1), a mediator of clearance. Livers of HF-fed mutant mice had high lipid content and elevated expression of lipogenic genes (peroxisome proliferator-activated receptor gamma, fatty acid synthase, and sterol regulatory element-binding protein 1c) and inflammatory markers (TNFalpha). Interestingly, mutant mice under HF showed elevated serum corticosterone, but their steatotic livers had reduced expression of gluconeogenic genes (phosphoenolpyruvate carboxy kinase, glucose 6 phosphatase, and pyruvate dehydrogenase kinase 4), whereas muscle and adipose expressed normal to elevated levels of glucocorticoid markers. These data suggest a state of glucocorticoid resistance arising from liver-specific loss of GR activity. Consistent with this hypothesis, reduced expression of gluconeogenic genes and CEACAM1 was observed in dexamethasone-treated FKBP52-deficient mouse embryonic fibroblast cells. We propose a model in which FKBP52 loss reduces GR control of gluconeogenesis, predisposing the liver to steatosis under HF-diet conditions attributable to a shunting of metabolism from glucose production to lipogenesis.
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614-5804, USA.
authors.forename: Manya
authors.initials: M
authors.lastname: Warrier
authors.forename: Terry D
authors.initials: TD
authors.lastname: Hinds
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Ledford
authors.forename: Harrison A
authors.initials: HA
authors.lastname: Cash
authors.forename: Payal R
authors.initials: PR
authors.lastname: Patel
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bowman
authors.forename: Lance A
authors.initials: LA
authors.lastname: Stechschulte
authors.forename: Weidong
authors.initials: W
authors.lastname: Yong
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Najjar
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Sanchez
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000235:genetics; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood; D004041:Dietary Fats / Q000494:pharmacology; D004198:Disease Susceptibility; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics*; D006943:Hyperglycemia / Q000139:chemically induced / Q000235:genetics; D006946:Hyperinsulinism / Q000139:chemically induced / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D004041:Dietary Fats; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4; D003345:Corticosterone