EFFECT OF THE Pro12Ala POLYMORPHISM OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR γ2 GENE ON LIPID PROFILE AND ADIPOKINES LEVELS IN OBESE SUBJECTS
Becer E1,2,*, Çırakoğlu A3
*Corresponding Author: Eda Becer, Ph.D., M.Sc., Department of Biochemistry, Faculty of Pharmacy, Near East University, Nicosia, Mersin 10, Turkey. Tel: +90-392-680-2000, Ext: 128. Fax:+90-392-680-2038. E-mail: edabecer@yahoo.com
page: 71

DISCUSSION

Peroxisome proliferator-activated receptor γ is a nuclear receptor that has a key role in energy storage, adipocyte differentiation, insulin sensitization and fatty acid metabolism [8]. To the best of our knowledge, this is the first report of the influence of Pro12Ala PPARγ gene polymorphism genotypes on chemerin levels in obese and non obese subjects. Our results showed no correlation between the Pro12Ala PPARγ gene polymorphism and BMI, waist-hip circumference, HOMA-IR, total cholesterol, LDL-cholesterol, HDL-cholesterol and fasting glucose levels in both obese and non obese groups. On the other hand, the Pro12Ala polymorphism showed a significant association with triglyceride, adiponectin and resistin levels particularly in the obese group. Furthermore, we showed that the PPARγ gene polymorphism was associated with leptin levels in both the obese and non obese groups. The PPARγ2 gene Pro12Ala polymorphism is the most studied genetic variant as potentially linked to the development of obesity. However, the results are still controversial. A number of studies have reported on the association of this variant with BMI and fat mass in different populations [17-19]. Ben Ali et al. [12] showed significant association between the PPARγ2 gene Pro12Ala polymorphism and obesity in non diabetic men of Tunisian origin. Also, Yao et al. [8] and Masud et al. [19] performed a meta-analysis to explain the association between Pro12Ala polymorphism and obesity. The results suggested that Pro12Ala polymorphism is a genetic modifier of obesity [8,19]. Contrary to these results, Gonzalez et al. [20] found a strong negative relationship between lower BMI. Deeb et al. [7] reported association of the Pro12Ala polymorphism in middle-aged non diabetic Finns, suggesting that the carriers of the alanine allele had significantly lower BMI. Buzzetti et al. [3] also reported that this PPARγ2 gene was not associated with high BMI in the Italian population. Moffett et al. [21] showed no significant association between the Pro12Ala polymorphism and BMI in Hispanic and non Hispanic subjects. In the German study, the authors failed to find an association between this polymorphism and obesity [22]. Additionally, in a meta-analysis study including six studies from different populations, it was shown that there was no association between the Pro12Ala PPARγ2 gene polymorphism and obesity [23]. As in other studies, our results showed no association between the PPARγ2 gene polymorphism and BMI in Turkish Cypriots. Thus, our results may suggest that discrepancies in association studies could be related to ethnic differences, life style, nutritional factors, effects of gender and pleiotropic genotype, may also affect energy homeostasis and BMI. Deeb et al. [7] first reported that the influence of the Pro12Ala polymorphism on lipoprotein lipase (LPL) gene expression is most likely due to an effect on a functional PPAR response element in the LPL promoter and the PPARγ2 isoform had lower transactivation capacity on the LPL gene in vitro [7]. In keeping with this result, Schneider et al. [24] demonstrated that the Pro12Ala substitution in PPARγ2 was associated with lower LPL activity in vivo. Moreover, Beamer et al. [18] showed that subjects with the alanine allele had higher triglyceride levels compared with PP wild-type genotype subjects, and Swarbrick et al. [22] observed higher levels of triglycerides in obese subjects with the alanine allele. In accordance with these previous findings, our results showed an association between the Pro12Ala polymorphism and triglyceride levels in obese subjects. The higher level of triglycerides seen only in the obese subjects with the Pro12Ala polymorphism may be due to larger adipose tissue mass, and therefore, relative intrinsic reduction of PPARγ2 activity. Leptin and PPARγ2 are two important adipose tissue factors involved in energy metabolism regulation. It has been shown that activation of PPARγ inhibit leptin gene expression in adipocytes [25]. Moreover, heterozygous PPARγ-deficient mice exhibit higher leptin levels than wildtype littermates [26]. Ben Ali et al. [12] also found an association between the Ala12 allele and higher levels of leptin in obese male subjects. Simón et al. [27] observed a increased serum leptin level in women with T2DM. In agreement with these studies, our results showed that subjects with the AA genotype for Pro12Ala in both the obese and non obese groups had significantly higher leptin levels than those with the PA and PP genotypes. It can be concluded that the Pro12Ala substitution on the structure of PPARγ2 may decrease functional antagonism effect of liganded PPARγ on the CCAAT/enhancer binding protein α (C/EBPα) transactivation of the leptin promoter. Peroxisome proliferator-activated receptor γ is a modulator of numerous genes in the mature adipocyte, including those encoding adipokines which have a variety of functions to regulate physiological processes [28]. In mammalian cells, the PPARγ and C/EBPα are the main regulators of adipocyte specific expression of adiponectin [29]. Adi-ponectin is known to be potential sensitizer of insulin for liver and muscle. Levels of this adipokine are negatively correlated with a measure of adiposity and decreased with obesity and insulin resistance [30]. The PPARγ is a positive regulator of adiponectin expression and enhance adi-ponectin synthesis from adipocytes. The association of the PPARγ2 gene Pro12Ala polymorphism with adiponectin level has been widely examined in various studies, yet the results are still controversial. Mousavinasab et al. [31] found that AA genotype was associated with elevated adi-ponectin levels in young Finnish men. Ben Ali et al. [12] and Bhatt et al. [32] showed no significant association between the Pro12Ala and adiponectin levels. Contrary to this result, Takata et al. [33] and Yamamoto et al. [34] reported significant association between the PPARγ2 Ala12 allele and low adiponectin levels in young and healthy Japanese, respectively. Additionally, VázquezDel Mercado et al. [35], found that carriers of the alanine allele were observed to have decreased adiponectin levels in obese group. Considering our results, which showed that subjects with the AA genotype for PPARγ2 in the obese group have significantly higher adiponectin levels than those with the PA and PP genotypes, one could then speculate that the Pro12Ala substitution could be related to decreased binding affinity to the cognate promoter element in adiponectin gene. Resistin is a potential link between obesity and insulin resistance or T2DM. To date, with respect to the resistin levels, one unique study demonstrated that the Pro12Ala polymorphism in Mexican-Mestizo population was not associated with resistin levels in both obese and non obese subjects [35]. In contrast, our results also showed that subjects with the AA genotype had significantly higher plasma resistin levels than the heterozygous PA and wildtype PP genotypes in obese subjects. In humans, resistin is expressed primarily by macrophages and PPARγ2 inhibits resistin synthesis [36]. The alanine allele was shown to have reduced efficiency in transactivating responsive promoter [7]. Thus, our results indicate that the alanine allele may decrease inhibition of resistin expression by PPARγ2 in obesity. All of the above suggests that high resistin and low adiponectin may cause insulin resistance and increase HOMA-IR levels in obese subjects who are carriers of the alanine allele. Peroxisome proliferator-activated receptor γ is regarded as the master regulator of adipocyte differantiation and it has close temporal relationship between chemerin during adipogenesis [37]. It has been demonstrated previously that knockdown of PPARγ expression abrogated both adipocyte differentiation and the induction of chemerin gene expression. Muruganandan et al. [38] demonstrated a direct role for PPARγ in regulating the expression of chemerin at the level of gene transcription. It has been reported that chemerin gene expression was decreased by PPARγ activation in mature bone marrow mesenchymal stem cell derivated adipocytes. Additionally, in vivo studies showed that PPARγ activation increased chemerin expression in white adipose tissue but not liver. Unfortunately, we found no published study of the association between Ala16Val PPARγ2 polymorphism genotypes and chemerin levels. Thus, this is the first study of the potential effect that substitution may cause impairment in PPARγ2 function by disturbing regulation of the Pro12Ala gene polymorphism on chemerin levels in obesity. Our results suggest that subjects with the AA genotype for Pro12Ala in both the obese and non obese groups had significantly higher plasma chemerin levels than those with the PA and PP genotypes. This shows that PPARγ2 carries the alanine allele at position 12, it seems less active than the proline counterpart. These data suggest that the alanine variant of PPARγ2 may lead to an adverse effect on inhibition of chemerin expression in mature adipocytes and it could also increase plasma chemerin levels. Further studies are also necessary to better understand this relationship. In the present study, the genotype and allele frequencies of obese and non obese groups were compared by the χ2 test, but no statistically significant differences were observed. There was no significant derivation of genotypic distribution from HWE in non obese subjects (p = 0.61). Whereas, the PPARγ2 genotype frequencies were shown to deviate from HWE (p = 0.0051) in the obese group. This showed that genetic diversity was deficient in this group because of the small number of sample size. The main limitation of this study was the lifestyle characteristics, which have an influence on the relationship between gene variants and phenotypes. Another weakness was the relatively limited sample size, lack of body fat mass % measurement and PPARγ2 expression levels. In conclusion, our results suggest that the PPARγ2 gene Pro12Ala polymorphism has no direct association with obesity but it does have significant influences on lipid profiles and adipokine expression. Based on the literature and our findings, the Pro12Ala polymorphism alone is not enough to be obese. Perhaps there is a cumulative effect in combining different factors like ethnicity, pleiotropic genotype effects and mitochondrial dysfunction, which altogether may regulate substrate metabolism, energy expenditure in the pathophysiology of obesity as well as roles in the mechanisms that affect adipogenesis and mature adipocyte function. In order to resolve this contradiction, further assessment of this with a larger cohort that includes all possible polymorphisms and environmental variables that might affect BMI, lipid metabolism and adipokine levels, is necessary. Conflict of Interest. The author declares no conflict of interests in this study. The authors alone are responsible for the content and writing of this article.



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