title: FKBP51 Null Mice Are Resistant to Diet-Induced Obesity and the PPARγ Agonist Rosiglitazone.
abstract: FK506-binding protein-51 (FKBP51) is a molecular cochaperone recently shown to be a positive regulator of peroxisome proliferator-activated receptor (PPAR)γ, the master regulator of adipocyte differentiation and function. In cellular models of adipogenesis, loss of FKBP51 not only reduced PPARγ 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 mice were resistant to weight gain, hepatic steatosis, 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 PPARγ 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 PPARγ-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 PPARγ in WAT and as a potential new target in the treatment of obesity and diabetes.
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Lance A
authors.initials: LA
authors.lastname: Stechschulte
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Bin
authors.initials: B
authors.lastname: Qiu
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Manya
authors.initials: M
authors.lastname: Warrier
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Hinds
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Man
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Hao
authors.initials: H
authors.lastname: Gu
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Yuxue
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Saja S
authors.initials: SS
authors.lastname: Khuder
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Lucia
authors.initials: L
authors.lastname: Russo
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Najjar
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Beata
authors.initials: B
authors.lastname: Lecka-Czernik
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Weidong
authors.initials: W
authors.lastname: Yong
authors.affiliation: Departments of Physiology and Pharmacology (L.A.S., M.W., T.D.H., S.S.K., L.R., S.M.N., B.L.-C., E.R.S.) and Orthopaedic Surgery (L.A.S., B.L.-C.) and the Center for Diabetes and Endocrine Research (L.A.S., M.W., T.D.H., S.K., L.R., S.M.N., B.L.-C., E.R.S.), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614-5804; Department of Gene and Development (B.Q., M.Z., H.G., Y.X., W.Y.), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China; and Department of Nutrition (M.W.), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina 27599.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Sanchez
mesh_terms: D050154:Adiposity; D000818:Animals; D004734:Energy Metabolism; D005234:Fatty Liver / Q000209:etiology; D018149:Glucose Intolerance; D050152:Intra-Abdominal Fat / Q000166:cytology; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology*; D047495:PPAR gamma / Q000502:physiology*; D000077154:Rosiglitazone; D022021:Tacrolimus Binding Proteins / Q000502:physiology*; D045162:Thiazolidinediones; D015430:Weight Gain; D000099159:Tacrolimus Binding Protein 5
chemical_list: D008055:Lipids; D047495:PPAR gamma; D000077154:Rosiglitazone; D022021:Tacrolimus Binding Proteins; D045162:Thiazolidinediones; D000099159:Tacrolimus Binding Protein 5