Genetic Polymorphisms in Peroxisome Proliferator-Activated Receptor δ Associated With Obesity

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. Three different PPARs, PPAR-␣, -␥, and -␦, have been characterized, and they are distinguished from each other by tissue distribution and cell activation. All PPARs are, to different extents, activated by fatty acids and derivatives. Recently, it has been shown that PPAR-␦ serves as a widespread regulator of fat burning, suggesting that it might be a potential target in the treatment of obesity and type 2 diabetes. In an effort to identify polymorphic markers in potential candidate genes for type 2 diabetes, we have sequenced PPAR-␦, including ؊1,500 bp of the 5 flanking region. Nine polymorphisms were identified in PPAR-␦: four in the intron, one in the 5 untranslated region (UTR), and four in the 3 UTR. Among identified polymorphisms, five common sites, including c.؊13454G>T, c.؊87T>C, c.2022؉12G>A, c.2629T>C, and c.2806C>G, were genotyped in subjects with type 2 diabetes and normal control subjects (n ‫؍‬ 702). The genetic associations with the risk of type 2 diabetes and metabolic phenotype were analyzed. No significant associations with the risk of type 2 diabetes were detected. However, several positive associations of PPAR-␦ polymorphisms with fasting plasma glucose and BMI were detected in nondiabetic control subjects. The genetic information about PPAR-␦ from this study would be useful for further genetic study of obesity, diabetes, and other metabolic diseases. Diabetes 53: 847-851, 2004 T he peroxisome proliferator-activated receptor (PPAR) superfamily includes receptors that mediate the size and number of peroxisomes produced by cells in response to a diverse group of chemicals of both biologic and nonbiologic origin (1). PPARs have been implicated in many normal and diseaserelated processes, including lipid metabolism, inflammation, embryo implantation, diabetes, and cancer (2). To date, three isotypes have been identified: PPAR-␣, -␥, and -␦ (also known as PPAR-␤ and NUC-1). PPARs bind to sequence-specific DNA response elements as a heterodimer with the retinoic acid receptor (3). Unlike the PPAR-␣ and -␥ receptors, little is known about the physiological role of the PPAR-␦ isoform. PPAR-␦ (MIM# 600409) was mapped to 6p21.2-p21.1 with 11 exons spanning 35 Kbp (4) and is expressed ubiquitously. It has been known as a potential downstream target of the adenomatous polyposis coli/␤-catenin/T-cell factor-4 tumor suppressor pathway (5), as well as shown to be experimentally activated by arachidonic and oleic acids and the peroxisome proliferator activator WY14643 (6). It has also been implicated in keratinocyte differentiation and wound healing and in mediating VLDL signaling of the macrophage (7-10). Recently, it was demonstrated that activation of PPAR-␦ promotes fatty acid oxidation and utilization in adipocytes and skeletal muscle cells, suggesting that PPAR-␦ serves as a widespread regulator of fat burning (11). Despite potential important roles in m...

Features of the metabolic syndrome are modulated by an interaction between the peroxisome proliferator-activated receptor-delta −87T>C polymorphism and dietary fat in French-Canadians

“…The frequency of the À87C allele was of 20.1% and was similar to the frequency observed in a sample of Korean subjects 15 and in a Scotland population with coronary heart disease (CHD) 16 but was slightly higher than that in healthy subjects from Sweden (15.6%). 14 Although these results must Abbreviations: BMI, body mass index; HDL, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PPAR, peroxisome proliferator-activated receptor.…”

“…Two previous studies performed by Skogsberg et al 14,16 have been performed with male subjects and found no association in one study and lower plasma HDL-C levels in À87C carriers in the other study. Another study performed by Shin et al 15 showed no association with plasma HDL-C levels. Unfortunately, these data were not analyzed separately by sex.…”

“…Although carriers of the -87C allele seem to be at lower risk of exhibiting the MS, the CHD and type 2 diabetes risk does not seem to be influenced by the presence of this variant. 15,16 Skogsberg et al 16 observed that homozygous for the À87C allele showed a trend toward higher risk of CHD but this result did not reach statistical significance. However, these studies did not take into account dietary fat intake, a nutritional factor involved both in the activation of PPAR-delta and in the development of the MS.…”

“…11,12 As for PPARa and PPARg, fatty acids are natural ligands of PPARdelta. 13 A polymorphism in the 5 0 untranslated region of the PPAR-delta gene has been identified, the À87T4C polymorphism (also named þ 294T4C), 14,15 and shown to be associated with the plasma lipid profile. 14,16 Transient transfection assays revealed that the À87C allele has higher transcription activity suggesting a greater PPAR-delta activity.…”

Variation in the peroxisome proliferator-activated receptor δ gene in relation to common metabolic traits in 7,495 middle-aged white people

“…The minor allele of the rs2016520 variant in exon 4 has inconsistently been associated with decreased fasting levels of HDL-cholesterol [15], increased LDL-cholesterol a Regression estimate±SE of the logarithm of HOMA-IR (pmol/l×mmol/l) with haplotype 1 (A-C) as base Haplotype frequencies were estimated using the EM algorithm and association with quantitative traits was evaluated by global and haplotypespecific score statistics ( p value) and simulation (p SIM ) [31] Estimates of the effect sizes of each haplotype were estimated by modelling the haplotype×phenotype interaction [32] [16,17] and increased fasting plasma glucose [37] or decreased BMI [20], even though some studies found no association [19,21]. Yet all studies were probably statistically underpowered, involving fewer than 1,000 participants.…”