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

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

Abbreviations: gWAT, gonadal white adipose tissue; PPAR, peroxisome proliferator–activated receptor; scWAT, subcutaneous white adipose tissue; WAT, white adipose tissue

Peroxisome proliferator–activated receptor (PPAR) is a key transcription factor facilitating fat deposition in adipose tissue through its proadipogenic and lipogenic actions. Human patients with dominant-negative mutations in PPAR display lipodystrophy and extreme insulin resistance. For this reason it was completely unexpected that mice harboring an equivalent mutation (P465L) in PPAR developed normal amounts of adipose tissue and were insulin sensitive. This finding raised important doubts about the interspecies translatability of PPAR-related findings, bringing into question the relevance of other PPAR murine models. Here, we demonstrate that when expressed on a hyperphagic ob/ob background, the P465L PPAR 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 PPAR mutation and the leptin-deficient state creates a mismatch between insufficient adipose tissue expandability and excessive energy availability, unmasking the deleterious effects of PPAR mutations on carbohydrate metabolism and replicating the characteristic clinical symptoms observed in human patients with dominant-negative PPAR mutations. Thus, adipose tissue expandability is identified as an important factor for the development of insulin resistance in the context of positive energy balance.

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