The Pro12Ala PPARgamma2 variant determines metabolism at the gene-environment interface.
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.
Heikkinen
Sami
S
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch, France.
Argmann
Carmen
C
Feige
Jérôme N
JN
Koutnikova
Hana
H
Champy
Marie-France
MF
Dali-Youcef
Nassim
N
Schadt
Eric E
EE
Laakso
Markku
M
Auwerx
Johan
J
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
D007328:Insulin; D008055:Lipids; D047495:PPAR gamma; D020033:Protein Isoforms; D005947:Glucose