The nuclear receptor cochaperone FKBP51 is required for diet‐induced visceral adiposity

Abstract

Nuclear receptors are hormone‐regulated transcription factors that form heterocomplexes with Hsp90 and several cochaperones, including FK506‐binding protein‐51 (FKBP51), FKBP52, PP5, and Cyp40. We have evidence that loss of FKBP51 increases glucocorticoid receptor (GR) and decreases peroxisome proliferator‐activated receptor‐γ (PPARγ) transcriptional activity. In this study, we investigate the hypothesis that loss of FKBP51 leads to reciprocal dysregulation of GR and PPARγ, thereby increasing the expression of genes regulating lipid oxidation and/or energy expenditure. FKBP51‐KO mice were subjected to a high fat diet, compared to wild‐type mice, FKBP51‐KO animals were resistant to diet‐induced obesity, with reduced visceral adiposity, serum triglyceride, and free fatty acids. Food consumption, insulin secretion and clearance, and hepatic lipid accumulation were unchanged. Gene profiling of adipose showed elevated expression of thermogenic genes in the KO mice. In vitro adipogenesis studies showed FKBP51‐KO cells to be highly resistant to differentiation and lipid accumulation. The phosphorylation states of GR were tested using phospho‐specific antibodies for serines 212, 220 and 234 – the major sites of hormone‐induced phosphorylation. Results show FKBP51 controls GR phosphorylation at serines 220 and 234. These investigations have uncovered FKBP51 as a key regulator of adipogenesis and thermogenesis and may serve as a new drug target in the treatment of obesity and related disorders.Supported by NIH grant DK70127 to E.R.S.