The Link Between Nutritional Status and Insulin Sensitivity Is Dependent on the Adipocyte-Specific Peroxisome Proliferator–Activated Receptor-γ2 Isoform Gema Medina-Gomez 1 , Sam Virtue 1 , Christopher Lelliott 1 , Romina Boiani 2 , Mark Campbell 1 , Constantinos Christodoulides 1 , Christophe Perrin 3 , Mercedes Jimenez-Linan 1 , Margaret Blount 1 , John Dixon 4 , Dirk Zahn 4 , Rosemary R. Thresher 4 , Sam Aparicio 4 , Mark Carlton 4 , William H. Colledge 1 , Mikko I. Kettunen 5 , Tuulikki Seppänen-Laakso 6 , Jaswinder K. Sethi 1 , Stephen O’Rahilly 1 , Kevin Brindle 5 , Saverio Cinti 2 , Matej Orešič 6 , Remy Burcelin 3 and Antonio Vidal-Puig 1 1 Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K. 2 Institute of Normal Human Morphology, Faculty of Medicine, Ancona University, Ancona, Italy 3 Centre National de la Recherche Scientifique-UMR 5018, Paul Sabatier University, Toulouse, France 4 Paradigm Therapeutics, Cambridge, U.K. 5 Department of Biochemistry, University of Cambridge, Cambridge, U.K. 6 VTT: Technical Research Centre of Finland, VTT Biotechnology, Espoo, Finland Address correspondence and reprint requests to Antonio Vidal-Puig, Department of Clinical Biochemistry, University of Cambridge/Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QR, U.K. E-mail: ajv22{at}cam.ac.uk Abstract The nuclear receptor peroxisome proliferator–activated receptor-γ (PPARγ) is critically required for adipogenesis. PPARγ exists as two isoforms, γ1 and γ2. PPARγ2 is the more potent adipogenic isoform in vitro and is normally restricted to adipose tissues, where it is regulated more by nutritional state than PPARγ1. To elucidate the relevance of the PPARγ2 in vivo, we generated a mouse model in which the PPARγ2 isoform was specifically disrupted. Despite similar weight, body composition, food intake, energy expenditure, and adipose tissue morphology, male mice lacking the γ2 isoform were more insulin resistant than wild-type animals when fed a regular diet. These results indicate that insulin resistance associated with ablation of PPARγ2 is not the result of lipodystrophy and suggests a specific role for PPARγ2 in maintaining insulin sensitivity independently of its effects on adipogenesis. Furthermore, PPARγ2 knockout mice fed a high-fat diet did not become more insulin resistant than those on a normal diet, despite a marked increase in their mean adipocyte cell size. These findings suggest that PPARγ2 is required for the maintenance of normal insulin sensitivity in mice but also raises the intriguing notion that PPARγ2 may be necessary for the adverse effects of a high-fat diet on carbohydrate metabolism. BAT, brown adipose tissue GTT, glucose tolerance test HFD, high-fat diet ITT, insulin tolerance test IRS1, insulin receptor substrate 1 LC/MS, liquid chromatography/mass spectrometry MRI, magnetic resonance imaging PPARγ, peroxisome proliferator–activated receptor-γ RPA, ribonuclease protection assay SREBP1c, sterol regulatory element–binding protein 1c WAT, white adipose tissue Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted February 21, 2005. Received November 22, 2004. DIABETES