title: The Pro12Ala PPARgamma2 variant determines metabolism at the gene-environment interface.
abstract: 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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch, France.
authors.forename: Sami
authors.initials: S
authors.lastname: Heikkinen
authors.forename: Carmen
authors.initials: C
authors.lastname: Argmann
authors.forename: Jérôme N
authors.initials: JN
authors.lastname: Feige
authors.forename: Hana
authors.initials: H
authors.lastname: Koutnikova
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Champy
authors.forename: Nassim
authors.initials: N
authors.lastname: Dali-Youcef
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D015992:Body Mass Index; D004032:Diet; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008136:Longevity; D051379:Mice; D009154:Mutation; D047495:PPAR gamma / Q000235:genetics* / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D008055:Lipids; D047495:PPAR gamma; D020033:Protein Isoforms; D005947:Glucose