Nature Genetics
20, 284 - 287 (1998)
doi:10.1038/3099
A Pro12Ala substitution in PPAR 2 associated with decreased receptor
activity, lower body mass index and improved insulin sensitivitySamir S. Deeb1, Lluis Fajas2, Masami Nemoto1, Jussi Pihlajamäki3, Leena Mykkänen3, Johanna Kuusisto3, Markku Laakso3, Wilfred Fujimoto1
& Johan Auwerx21
Departments of Medicine and Genetics, University of
Washington, Seattle, Washington 98195,
USA. 2
U.325 INSERM, Département d'Athérosclérose,
Institut Pasteur, 59019 Lille, France. 3
Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
Correspondence should be addressed to Samir S. Deeb (deeb@genetics.washington.edu)The peroxisome proliferator-activated receptor- (PPAR) is
a transcription factor that has a pivotal role in adipocyte differentiation
and expression of adipocyte-specific genes1,
3. The PPAR1
and 2 isoforms result from alternative splicing4 and
have ligand-dependent and -independent activation domains. PPAR2 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 PPAR1. Insulin
stimulates the ligand-independent activation of PPAR1 and 2
(ref. 5), however, obesity and nutritional factors
only influence the expression of PPAR2 in human adipocytes6.
Here, we report that a relatively common Pro12Ala substitution in PPAR2
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 PPAR2
Ala allele showed decreased binding affinity to the cognate promoter element
and reduced ability to transactivate responsive promoters. These findings
suggest that the PPAR2 Pro12Ala variant may contribute to the observed
variability in BMI and insulin sensitivity in the general population.
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