A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity
Open accessAbstract
The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. The PPARgamma1 and gamma2 isoforms result from alternative splicing and have ligand-dependent and -independent activation domains. PPARgamma2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5-10-fold more effective than that of PPARgamma1. Insulin stimulates the ligand-independent activation of PPARgamma1 and gamma2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARgamma2 in human adipocytes. Here, we report that a relatively common Pro12Ala substitution in PPARgamma2 is associated with lower body mass index (BMI; P=0.027; 0.015) and improved insulin sensitivity among middle-aged and elderly Finns. A significant odds ratio (4.35, P=0.028) for the association of the Pro/Pro genotype with type 2 diabetes was observed among Japanese Americans. The PPARgamma2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARgamma2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.
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The risk of false negatives was illustrated by T2D and the Pro12 → Ala polymorphism in PPARγ: larger studies produced strong and consistent evidence of increased risk by a factor of 1.2, while negative studies lacked adequate power.
“Whereas an initial positive report (61) had not been confirmed in four modest-sized replication studies, larger studies produced strong and consistent evidence of increased risk by a factor of 1.2 (62, 63). The negative studies were actually consistent with the level of increased risk, but simply lacked adequate power to detect it.”
From Genetic Mapping in Human Disease (2008) · cites this paper as [61]
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- Authors
- Deeb, S. S., Fajas, L., Nemoto, M., Pihlajamäki, J., Mykkänen, L., Kuusisto, J., Laakso, M., Fujimoto, W., & Auwerx, J.
- Affiliations
- University of Washington (US)
- Kuopio University Hospital (FI)
- Inserm (FR)
- Corresponding author
- Deeb, Samir S.
- Venue
- Nature Genetics
- Published
- 1998-11
- Volume
- 20
- Issue
- 3
- Pages
- 284-287
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- DOI
- 10.1038/3099
- OpenAlex
- W1527649416
- Cited by
- 1,319
- References
- 30
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 14 · 2023: 18 · 2022: 20 · 2021: 26 · 2020: 23 · 2019: 23 · 2018: 37 · 2017: 31 · 2016: 31 · 2015: 45 · 2014: 57 · 2013: 56 · 2012: 69
- FWCI
- 13.25
- Type
- journal article
- Language
- en
- Open access
- green
- infoscience.epfl.ch
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- National Heart, Lung, and Blood Institute (P01HL030086, HL3-0086)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK3117, DK-17047, P30DK017047)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Keywords
- PPARγ2, Pro12Ala polymorphism, single nucleotide polymorphisms, body mass index, insulin sensitivity, type 2 diabetes, adipocytes, transcriptional activity, promoter binding affinity, obesity, genetic association
- MeSH terms
- Adult, Aged, Alleles, Base Sequence, Diabetes Mellitus, Type 2, Female, Finland, Gene Frequency, Genotype, Humans, Insulin Resistance, Male, Middle Aged, Promoter Regions, Genetic, Transcription Factors, Genetic Variation, Transcriptional Activation, Body Mass Index, DNA Primers, Receptors, Cytoplasmic and Nuclear, Amino Acid Substitution
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