FKBP51 null mice are resistant to diet-induced obesity and the ppary agonist rosiglitazone

Lance A. Stechschulte, Bin Qiu, Manya Warrier, Terry D. Hinds, Man Zhang, Hao Gu, Yuxue Xu, Saja S. Khuder, Lucia Russo, Sonia M. Najjar, Beata Lecka-Czernik, Weidong Yong, Edwin R. Sanchez

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

FK506-binding protein-51 (FKBP51) is a molecular cochaperone recently shown to be a positive regulator of peroxisome proliferator-activated receptor (PPAR)7, the master regulator of adipocyte differentiation and function. In cellular models of adipogenesis, loss of FKBP51 not only reduced PPAR7 activity but also reduced lipid accumulation, suggesting that FKBP51 knock-out (KO) mice might have insufficient development of adipose tissue and lipid storage ability. This model was tested by examining wild-type (WT) and FKBP51-KO mice under regular and high-fat diet conditions. Under both diets, FKBP51-KO micewere resistantto weight gain, hepaticsteatosis, and had greatly reduced white adipose tissue (WAT) but higher amounts of brown adipose tissue. Under high-fat diet, KO mice were highly resistant to adiposity and exhibited reduced plasma lipids and elevated glucose and insulin tolerance. Profiling of perigonadal and sc WAT revealed elevated expression of brown adipose tissue lineage genes in KO mice that correlated increased energy expenditure and a shift of substrate oxidation to carbohydrates, as measured by indirect calorimetry. To directly test PPAR7 involvement, WT and KO mice were fed rosiglitazone agonist. In WT mice, rosiglitazone induced whole-body weight gain, increased WAT mass, a shift of substrate oxidation to lipids, and elevated expression of PPAR7-regulated lipogenic genes in WAT. In contrast, KO mice had reduced rosiglitazone responses for these parameters. Our results identify FKBP51 as an important regulator of PPARγin WAT and as a potential new target in the treatment of obesity and diabetes.

Original languageEnglish
Pages (from-to)3888-3900
Number of pages13
JournalEndocrinology
Volume157
Issue number10
DOIs
StatePublished - 2016

Bibliographical note

Publisher Copyright:
Copyright © 2016 by the Endocrine Society.

ASJC Scopus subject areas

  • Endocrinology

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