Leptin Deficiency Unmasks the Deleterious Effects of Impaired Peroxisome Proliferator–Activated Receptor γ Function (P465L PPARγ) in Mice

Leptin Deficiency Unmasks the Deleterious Effects of Impaired Peroxisome Proliferator–Activated Receptor γ Function (P465L PPARγ) in Mice Sarah L. Gray 1 , Edoardo Dalla Nora 1 , Johannes Grosse 2 , Monia Manieri 3 , Tobias Stoeger 4 , Gema Medina-Gomez 1 , Keith Burling 1 , Sigrid Wattler 2 , Andreas Russ 5 , Giles S.H. Yeo 1 , V. Krishna Chatterjee 6 , Stephen O’Rahilly 1 6 , Peter J. Voshol 7 , Saverio Cinti 3 and Antonio Vidal-Puig 1 6 1 Department of Clinical Biochemistry, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K 2 Ingenium Pharmaceuticals, Martinsried, Germany 3 Department of Normal Human Morphology, Faculty of Medicine, Ancona University, Ancona, Italy 4 GSF-National Research Center for Environment and Health, Institute of Inhalation Biology, Muenchen-Neuherberg, Germany 5 Genetics Unit, Department of Biochemistry, University of Oxford, Oxford, U.K 6 Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K 7 TNO-Prevention and Health, Division VBO, Leiden, the Netherlands 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 Peroxisome proliferator–activated receptor (PPAR)γ is a key transcription factor facilitating fat deposition in adipose tissue through its proadipogenic and lipogenic actions. Human patients with dominant-negative mutations in PPARγ display lipodystrophy and extreme insulin resistance. For this reason it was completely unexpected that mice harboring an equivalent mutation (P465L) in PPARγ developed normal amounts of adipose tissue and were insulin sensitive. This finding raised important doubts about the interspecies translatability of PPARγ-related findings, bringing into question the relevance of other PPARγ murine models. Here, we demonstrate that when expressed on a hyperphagic ob/ob background, the P465L PPARγ mutant grossly exacerbates the insulin resistance and metabolic disturbances associated with leptin deficiency, yet reduces whole-body adiposity and adipocyte size. In mouse, coexistence of the P465L PPARγ mutation and the leptin-deficient state creates a mismatch between insufficient adipose tissue expandability and excessive energy availability, unmasking the deleterious effects of PPARγ mutations on carbohydrate metabolism and replicating the characteristic clinical symptoms observed in human p