Susceptibility to diet-induced hepatic steatosis and glucocorticoid resistance in FK506-binding protein 52-deficient mice

Manya Warrier, Terry D. Hinds, Kelly J. Ledford, Harrison A. Cash, Payal R. Patel, Thomas A. Bowman, Lance A. Stechschulte, Weidong Yong, Weinian Shou, Sonia M. Najjar, Edwin R. Sanchez

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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 placedona high-fat (HF) dietknown 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 antigenrelated 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 γ, fatty acid synthase, and sterol regulatory element-binding protein 1c) and inflammatory markers (TNFα). 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.

Original languageEnglish (US)
Pages (from-to)3225-3236
Number of pages12
JournalEndocrinology
Volume151
Issue number7
DOIs
StatePublished - Jul 1 2010

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ASJC Scopus subject areas

  • Endocrinology

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Warrier, M., Hinds, T. D., Ledford, K. J., Cash, H. A., Patel, P. R., Bowman, T. A., Stechschulte, L. A., Yong, W., Shou, W., Najjar, S. M., & Sanchez, E. R. (2010). Susceptibility to diet-induced hepatic steatosis and glucocorticoid resistance in FK506-binding protein 52-deficient mice. Endocrinology, 151(7), 3225-3236. https://doi.org/10.1210/en.2009-1158