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The Link Between Nutritional Status and Insulin Sensitivity Is Dependent on the Adipocyte-Specific Peroxisome Proliferator–Activated Receptor-2 Isoform

Gema Medina-Gomez¹, Sam Virtue¹, Christopher Lelliott¹, Romina Boiani², Mark Campbell¹, Constantinos Christodoulides¹, Christophe Perrin³, Mercedes Jimenez-Linan¹, Margaret Blount¹, John Dixon⁴, Dirk Zahn⁴, Rosemary R. Thresher⁴, Sam Aparicio⁴, Mark Carlton⁴, William H. Colledge¹, Mikko I. Kettunen⁵, Tuulikki Seppänen-Laakso⁶, Jaswinder K. Sethi¹, Stephen O’Rahilly¹, Kevin Brindle⁵, Saverio Cinti², Matej Orei⁶, Remy Burcelin³, and Antonio Vidal-Puig¹

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

The nuclear receptor peroxisome proliferator–activated receptor- (PPAR) is critically required for adipogenesis. PPAR exists as two isoforms, 1 and 2. PPAR2 is the more potent adipogenic isoform in vitro and is normally restricted to adipose tissues, where it is regulated more by nutritional state than PPAR1. To elucidate the relevance of the PPAR2 in vivo, we generated a mouse model in which the PPAR2 isoform was specifically disrupted. Despite similar weight, body composition, food intake, energy expenditure, and adipose tissue morphology, male mice lacking the 2 isoform were more insulin resistant than wild-type animals when fed a regular diet. These results indicate that insulin resistance associated with ablation of PPAR2 is not the result of lipodystrophy and suggests a specific role for PPAR2 in maintaining insulin sensitivity independently of its effects on adipogenesis. Furthermore, PPAR2 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 PPAR2 is required for the maintenance of normal insulin sensitivity in mice but also raises the intriguing notion that PPAR2 may be necessary for the adverse effects of a high-fat diet on carbohydrate metabolism.

Abbreviations: 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; PPAR, peroxisome proliferator–activated receptor-; RPA, ribonuclease protection assay; SREBP1c, sterol regulatory element–binding protein 1c; WAT, white adipose tissue

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