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

Sami Heikkinen; Carmen Argmann; Jérôme N. Feige; Hana Koutnikova; Marie France Champy; Nassim Dali-Youcef; Eric E. Schadt; Markku Laakso; Johan Auwerx

doi:10.1016/j.cmet.2008.11.007

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

Sami Heikkinen, Carmen Argmann, Jérôme N. Feige, Hana Koutnikova, Marie France Champy, Nassim Dali-Youcef, Eric E. Schadt, Markku Laakso, Johan Auwerx

Research output: Contribution to journal › Article › peer-review

62 Scopus citations

Abstract

The metabolic impact of the common peroxisome proliferator-activated receptor gamma isoform 2 (PPARγ2) 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 Pparγ2 as an important modulator in metabolic control that strongly depends on the metabolic context.

Original language	English
Pages (from-to)	88-98
Number of pages	11
Journal	Cell Metabolism
Volume	9
Issue number	1
DOIs	https://doi.org/10.1016/j.cmet.2008.11.007
State	Published - 7 Jan 2009
Externally published	Yes

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HUMDISEASE

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title = "The Pro12Ala PPARγ2 Variant Determines Metabolism at the Gene-Environment Interface",

abstract = "The metabolic impact of the common peroxisome proliferator-activated receptor gamma isoform 2 (PPARγ2) 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 Pparγ2 as an important modulator in metabolic control that strongly depends on the metabolic context.",

keywords = "HUMDISEASE",

author = "Sami Heikkinen and Carmen Argmann and Feige, {J{\'e}r{\^o}me N.} and Hana Koutnikova and Champy, {Marie France} and Nassim Dali-Youcef and Schadt, {Eric E.} and Markku Laakso and Johan Auwerx",

note = "Funding Information: We acknowledge grant support of the NIH (DK067320-01), the European Union (Eugene2; LSHM-CT-2004-512013), CNRS, INSERM, ULP, the H{\^o}pital Universitaire de Strasbourg, EPFL, Merck Research Laboratories, and the Academy of Finland (grant number 124243). We thank the members of the Auwerx Laboratory and Doctors Thomas Vogt, Nancy Thornberry, and Michael Coon for helpful discussions and support. ",

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doi = "10.1016/j.cmet.2008.11.007",

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T1 - The Pro12Ala PPARγ2 Variant Determines Metabolism at the Gene-Environment Interface

AU - Heikkinen, Sami

AU - Argmann, Carmen

AU - Feige, Jérôme N.

AU - Koutnikova, Hana

AU - Champy, Marie France

AU - Dali-Youcef, Nassim

AU - Schadt, Eric E.

AU - Laakso, Markku

AU - Auwerx, Johan

N1 - Funding Information: We acknowledge grant support of the NIH (DK067320-01), the European Union (Eugene2; LSHM-CT-2004-512013), CNRS, INSERM, ULP, the Hôpital Universitaire de Strasbourg, EPFL, Merck Research Laboratories, and the Academy of Finland (grant number 124243). We thank the members of the Auwerx Laboratory and Doctors Thomas Vogt, Nancy Thornberry, and Michael Coon for helpful discussions and support.

PY - 2009/1/7

Y1 - 2009/1/7

N2 - The metabolic impact of the common peroxisome proliferator-activated receptor gamma isoform 2 (PPARγ2) 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 Pparγ2 as an important modulator in metabolic control that strongly depends on the metabolic context.

AB - The metabolic impact of the common peroxisome proliferator-activated receptor gamma isoform 2 (PPARγ2) 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 Pparγ2 as an important modulator in metabolic control that strongly depends on the metabolic context.

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SP - 88

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JO - Cell Metabolism

JF - Cell Metabolism

IS - 1

ER -

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

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Keywords

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