The role of PPARγ in high-fat diet-induced obesity and insulin resistance (original) (raw)
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Diabetologia, 1999
Aims/hypothesis. Recently a mutation in the coding sequence of the adipocyte specific isoform peroxisome proliferator-activated receptor γ2 (PPARγ2) was described, leading to the substitution of Proline to Alanine at codon 12. Mutations in PPARγ2 could have a role in people who are at increased risk for the development of obesity and Type II (non-insulin-dependent) diabetes mellitus. Methods. Non-diabetic first-degree relatives (n = 108) of subjects with Type II diabetes were characterized by oral glucose tolerance tests and euglycaemic hyperinsulinaemic glucose clamp to determine insulin sensitivity. Results. We found 75 (69 %) probands without the PPARγ ProAla12 substitution, 28 heterozygotes (26 %) and 5 (4 %) homozygotes. When the whole group was analysed for an association between the mutation and insulin sensitivity, no statistical significance could be shown. Only in the group with severe obesity more than 30 kg/m2, an association (p = 0.016) of the polymorphism with an increase in insulin sensitivity was found. Conclusion/interpretation. These observations suggest that the mutation in the PPARγ2 molecule may have a role in subgroups prone to the development of obesity and Type II diabetes. [Diabetologia (1999) 42: 758–762]
Nature genetics, 1998
The peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes 1-3 . The PPARγ1 and γ2 isoforms result from alternative splicing 4 and have ligand-dependent and -independent activation domains. PPARγ2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5−10fold more effective than that of PPARγ1. Insulin stimulates the ligand-independent activation of PPARγ1 and γ2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARγ2 in human adipocytes 6 . Here, we report that a relatively common Pro12Ala substitution in PPARγ2 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 PPARγ2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARγ2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.
International Journal of Obesity, 2000
OBJECTIVE: To determine the extent of variation in the gene for peroxisome proliferator activated receptor g (PPARg) in patients with morbid obesity. SUBJECTS: Two hundred morbidly obese patients who underwent gastric banding surgery and 192 healthy blood donors. Diabetics were excluded. EXPERIMENTAL: The frequency of the P115Q and P12A variants in the PPARg gene was determined. Single strand conformational polymorphism (SSCP) analysis was performed on all exons, exonaintron boundaries and part of the promoter of the PPARg gene on a sub-group of 67 morbid obese patients. RESULTS: None of the morbid patients or the blood donors were carriers of the P115Q mutation. The frequency of the P12A polymorphism did not differ signi®cantly between morbid obese patients and controls and there was no statistically signi®cant association between P12A and BMI. Male blood donors who were A12A homozygotes had statistically signi®cant higher serum leptin concentrations (P 0.001). Mutation screening revealed that one patient had a T ?G transversion at 7 208 in the promoter of PPARg-2, two had silent mutations, one a T?C transition in the third base of codon 144 and the other a C?T transition in codon 297. The fourth patient had a CGC?TGC transition in codon 316 resulting in the replacement of an arginine with a cysteine. This mutation was not found in any other morbidly obese patient. CONCLUSION: Variation in the PPARg gene is unlikely to play a major role in the development of morbid obesity.
Journal of Molecular Medicine, 2002
The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) γ 2 gene is associated with a reduced risk of type 2 diabetes. A beneficial effect on insulin sensitivity is reported in some but not all populations. It is possible that this genetic variant produces a characteristic phenotype only against a certain genetic background. We therefore tested the hypothesis that carriers of the Ala allele of PPARγ 2 exhibit a different phenotype against the background of the Gly972Arg polymorphism in the insulin receptor substrate (IRS) 1. We determined insulin sensitivity in the four combinations defined by the absence or presence of the polymorphic allele (healthy, glucose tolerant subjects), by the oral glucose tolerance test (OGTT; using a validated index, n=318) and hyperinsulinemic clamp (n=201). Insulin sensitivity was not or was only marginally different between Pro/Pro and X/Ala in the overall population. Interestingly, using the OGTT index, insulin sensitivity was significantly greater in X/Ala (PPARγ 2 ) + X/Arg (IRS-1) than in Pro/Pro (PPARγ 2 ) + X/Arg (IRS-1). On the other hand, insulin sensitivity was similar in the X/Ala (PPARγ 2 ) + Gly/Gly (IRS-1 972) and the Pro/Pro (PPARγ 2 ) + Gly/Gly (IRS-1). The results were practically identical using insulin sensitivity from the clamp. In conclusion, the Arg972 (IRS-1) background produced a marked difference in insulin sensitivity between X/Ala and Pro/Pro (PPARγ) which was not present in the whole population or against the Gly972 (IRS-1) background. This suggests that the Ala allele of PPARγ 2 becomes particularly advantageous against the background of an additional, possibly disadvantageous genetic polymorphism. Allowing for gene-gene interaction effects may reveal novel information regarding metabolic effects of genetic variants.
British Journal of Nutrition, 2007
The PPARg Pro12Ala polymorphism has been associated in several studies with a decreased risk of obesity, type 2 diabetes and insulin resistance. Weak hints are available about the influence of PPARg Pro12Ala on postprandial metabolism. In 708 men, aged 45 to 65 years the PPARg2 Pro12Ala genotypes were determined and postprandial TAG, insulin, glucose and NEFA after a standardized mixed fat meal and insulin and glucose after a glucose load (oral glucose tolerance test; OGTT) were assessed. Using the total sample, we did not find a significant impact of the genotype on the postprandial metabolism. In the subgroup with BMI , 30 kg/m 2 , fasting and postprandial TAG and insulin levels as well as homeostasis model assessment of insulin resistance (HOMA) were significantly lower in the Ala12Ala group than in the Pro12Pro group after the mixed meal. In contrast, the groups did not differ in insulin levels and HOMA after the OGTT. To investigate if differences between a fat-containing meal and OGTT are caused by adiponectin, we examined a BMI-and age-matched subgroup. No differences were found between the genotypic groups. The effects of the PPARg2 polymorphism on insulin sensitivity are mediated by affluent dietary fat. We did not find evidence that adiponectin as a fatty-acid-dependent adipocyte factor is a causative factor for this phenomenon. PPARg2 Pro12Ala: Insulin resistance: Type 2 diabetes: Single nucleotide polymorphism: Adiponectin * Corresponding author: Dr Ulf Helwig, fax þ49 431 609 2472, email ulf.helwig@bfel.de Abbreviations: AUC, area under the curve; HOMA, homeostasis model assessment of insulin resistance; OGTT, oral glucose tolerance test.
The role of the PPARG (Pro12Ala) common genetic variant on type 2 diabetes mellitus risk
2021
Type 2 diabetes (T2DM) prevalence has been rapidly increasing in the last decades. T2DM pathogenesis is related to insulin resistance and beta-cell dysfunction. Peroxisome proliferator-activated receptor gamma (PPARG) is concerned about T2DM risk through the involvement in adipocyte differentiation and energy homeostasis. The present study aimed to find the risk associated with a common genetic variant (Pro12Ala) of the PPARG gene in the development of T2DM in a group of the Iranian population. Totally, 149 patients with T2DM and 96 healthy individuals were recruited in this case–control study. The genotyping of the genetic variant was carried out using the polymerase chain reaction (PCR) followed by Sanger sequencing. No significant difference is observed between the CG and GG genotypes frequency of the PPARG variant (P = 0.17) in T2DM patient and the control groups. Furthermore, the frequency of the G allele was similar between case and control groups. The Pro12Ala variant may dec...
Clinical Chemical Laboratory Medicine, 2000
The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-g2 (PPARg-2) gene has been variably associated with insulin resistance, obesity and type 2 diabetes in several populations. However, this association has not been studied in Iranian subjects and we hypothesized that this variation might be associated with insulin resistance, type 2 diabetes and related metabolic traits in this population. Methods: The Pro12Ala genotypes were determined by PCR-restriction fragment length polymorphism in 696 unrelated subjects including 412 non-diabetic controls and 284 type 2 diabetic patients. Results: The frequency of the Ala allele was 9.4% and 5.9% in controls and type 2 diabetic subjects, respec-tively wadjusted odds ratio (OR) 0.457, ps0.005x. The Ala allele did not show a significant effect on anthropometric and biochemical parameters in the type 2 diabetic group, whereas in non-diabetic subjects, carriers of the Ala allele had significantly lower fasting insulin (ps0.007) and homeostasis model assessment of insulin resistance (HOMA-IR) (ps0.009) levels compared to Pro/Pro subjects. Multivariate logistic regression analysis showed that Pro12Ala polymorphism was an independent determinant of type 2 diabetes in this population.