Lance A. Stechschulte, Bin Qiu, Manya Warrier, Terry D. Hinds, Jr., Man Zhang, Hao Gu, Yuxue Xu, Saja S. Khuder, Lucia Russo, Sonia M. Najjar,
Beata Lecka-Czernik, Weidong Yong, and Edwin R. Sanchez (2016). FKBP51 Null Mice Are Resistant to Diet-Induced Obesity and the PPAR Agonist Rosiglitazone. Endocrinology, 1-14.
Departments of Physiology & Pharmacology and Orthopaedic Surgery and the Center for Diabetes and Endocrine Research,
University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614; Department of Gene and Development,
Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China 100021
Department of Nutrition, Nutrition Research Institute, University of N Carolina at Chapel Hill, Kannapolis, NC.
FK506-binding protein-51 (FKBP51) is a molecular cochaperone recently shown to be a positive
regulator of peroxisome proliferator-activated receptor- (PPAR) – the master regulator of adipocyte
differentiation and function. In cellular models of adipogenesis, loss of FKBP51 not only
reduced PPAR activity, but also reduced lipid accumulation, suggesting that FKBP51 null (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 (RD) and high-fat (HF) diet
conditions. Under both diets, FKBP51-KO mice were resistant to weight gain, hepatic steatosis and
had greatly reduced white adipose tissue (WAT), but higher amounts of brown adipose tissue
(BAT). Under HF diet, KO mice were highly resistant to adiposity and exhibited reduced plasma
lipids and elevated glucose and insulin tolerance. Profiling of perigonadal and subcutaneous WAT
revealed elevated expression of BAT 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 PPAR 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 PPAR- regulated lipogenic genes in WAT tissue. In
contrast, KO mice had reduced rosiglitazone responses for these parameters. Our results identify
FKBP51 as an important regulator of PPAR in WAT tissue and as a potential new target in the
treatment of obesity and diabetes.