The Pro12Ala PPARγ2 Variant Determines Metabolism at the Gene-Environment Interface

Sami Heikkinen (1, 2) , Carmen Argmann (1) , Jérôme Feige (1) , Hana Koutnikova (1, 3) , Marie-France Champy (3) , Nassim Dali-Youcef (4) , Eric Schadt (5) , Markku Laakso (2) , Johan Auwerx (6, 4, 3, 1)

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 University of Kuopio
3 ICS - Institut Clinique de la Souris
4 HUS - Les Hôpitaux Universitaires de Strasbourg
5 Rosetta Inpharmatics LLC
6 EPFL - Ecole Polytechnique Fédérale de Lausanne

The metabolic impact of the common peroxisome proliferator-activated receptor gamma isoform 2 (PPARgamma2) variant Pro12Ala in human populations has been widely debated. We demonstrate, using a Pro12Ala knockin model, that on chow diet, Ala/Ala mice are leaner, have improved insulin sensitivity and plasma lipid profiles, and have longer lifespans. Gene-environment interactions played a key role as high-fat feeding eliminated the beneficial effects of the Pro12Ala variant on adiposity, plasma lipids, and insulin sensitivity. The underlying molecular mechanisms involve changes in cofactor interaction and adiponectin signaling. Altogether, our results establish the Pro12Ala variant of Ppargamma2 as an important modulator in metabolic control that strongly depends on the metabolic context.

Domaines: Sciences du Vivant [q-bio]

Sami Heikkinen, Carmen Argmann, Jérôme Feige, Hana Koutnikova, Marie-France Champy, et al.. The Pro12Ala PPARγ2 Variant Determines Metabolism at the Gene-Environment Interface. Cell Metabolism, 2009, 9 (1), pp.88-98. ⟨10.1016/j.cmet.2008.11.007⟩. ⟨hal-03807865⟩