Resistin Gene Research Articles

Polymorphisms in 5′-flanking regions of genes encoding adiponectin, leptin, and resistin are not associated with obesity of Polish children and adolescents

Genes encoding adipokines are important functional candidates for development of obesity. In this study we screened for polymorphism 5'-flanking regions of the adiponectin (ADIPOQ), leptin (LEP) and resistin (RETN) genes in a cohort of Polish obese children and adolescents (n = 243) and a control group of non-obese adults (n = 100). Altogether 13 SNPs (single nucleotide polymorphisms) and 1 InDel (insertion/deletion polymorphism) were found. Among them five polymorphisms, localized in the LEP gene, turned out to be novel, but their distribution was insufficient for association studies. We found no consistent evidence for association between obesity and the SNPs demonstrating minor allele frequency (MAF) above 0.2 (ADIPOQ: -11377C>G, LEP: -2548C>T, 19A>G, RETN: -1300G>A, -1258C>T, -420C>G). Comparison of polymorphisms distribution in patients and control group suggested association with ADIPOQ -11377C>G (Pearson test P = 2.76 × 10(-11)), however, we did not observe any effect of this polymorphism on BMI or relative BMI (RBMI) within obese patients (P = 0.41). We conclude that the tested SNPs are not useful markers of childhood and adolescence obesity in Polish population.

Adipocyte-derived microvesicles contain RNA that is transported into macrophages and might be secreted into blood circulation

We have recently found that 3T3-L1 adipocytes secrete microvesicles, known as adipocyte-derived microvesicles (ADMs), with angiogenic activity. In this study, we found that ADMs contain RNA without typical 28S and 18S ribosomal RNA inside the vesicles. Microarray analysis revealed that ADMs contain approximately 7000 mRNAs and 140 microRNAs. Most of transcripts for adipocyte-specific and dominant genes were contained in the ADMs, and their abundance was mostly correlated with that in the donor cells. Abundance of adipocyte-related microRNAs was also mostly correlated with that in the donor cells. ADMs mediated transport of adiponectin and resistin gene transcripts into RAW264.7 macrophages. Moreover, adipocyte-specific gene transcripts such as adiponectin, resistin, and PPARγ2 were found in microvesicles isolated from rat serum. Thus, ADM might play a role as a novel intercellular communication tool by transporting RNA in paracrine and possibly endocrine manners.

Momordica Charantia (Bitter Melon) Inhibits Primary Human Adipocyte Differentiation by Modulating Adipogenic genes

Momordica charantia or bitter melon (BM) that is traditionally used to treat diabetes and complications has been demonstrated to alleviate hyperglycemia as well as reduce adiposity in rodents. The objective of our study was to investigate the effects of BM juice (BMJ) on lipid accumulation and adipocyte differentiation factors in primary human preadipocytes and differentiated adipocytes. Preadipocytes treated with varying concentrations of BMJ during differentiation significantly reduced lipid accumulation as well as the mRNA expression of peroxisome proliferator‐associated receptor (PPAR), sterol regulatory element‐binding protein 1c (SREBP‐1c) and resistin genes. Similarly, differentiated adipocytes treated with BMJ for 48 h demonstrated reduced lipid accumulation, perilipin mRNA expression, and increased lipolysis. Our data suggests that BM is a potent inhibitor of lipogenesis and stimulator of lipolysis activity in primary human adipocytes. BMJ may therefore prove to be an effective complementary or alternative therapy to induce anti‐obesity effects in humans. [Grants: NCCAM (R21AT003719), RCMI, NCRR (G12RRAI03061), NIH, and Hawaii Community Foundation (20041652)].

Transcription of human resistin gene involves an interaction of Sp1 with peroxisome proliferator-activating receptor gamma (PPARgamma).

BackgroundResistin is a cysteine rich protein, mainly expressed and secreted by circulating human mononuclear cells. While several factors responsible for transcription of mouse resistin gene have been identified, not much is known about the factors responsible for the differential expression of human resistin.Methodology/Principal FindingWe show that the minimal promoter of human resistin lies within ∼80 bp sequence upstream of the transcriptional start site (−240) whereas binding sites for cRel, CCAAT enhancer binding protein α (C/EBP-α), activating transcription factor 2 (ATF-2) and activator protein 1 (AP-1) transcription factors, important for induced expression, are present within sequences up to −619. Specificity Protein 1(Sp1) binding site (−276 to −295) is also present and an interaction of Sp1 with peroxisome proliferator activating receptor gamma (PPARγ) is necessary for constitutive expression in U937 cells. Indeed co-immunoprecipitation assay demonstrated a direct physical interaction of Sp1 with PPARγ in whole cell extracts of U937 cells. Phorbol myristate acetate (PMA) upregulated the expression of resistin mRNA in U937 cells by increasing the recruitment of Sp1, ATF-2 and PPARγ on the resistin gene promoter. Furthermore, PMA stimulation of U937 cells resulted in the disruption of Sp1 and PPARγ interaction. Chromatin immunoprecipitation (ChIP) assay confirmed the recruitment of transcription factors phospho ATF-2, Sp1, Sp3, PPARγ, chromatin modifier histone deacetylase 1 (HDAC1) and the acetylated form of histone H3 but not cRel, C/EBP-α and phospho c-Jun during resistin gene transcription.ConclusionOur findings suggest a complex interplay of Sp1 and PPARγ along with other transcription factors that drives the expression of resistin in human monocytic U937 cells.

A at Single Nucleotide Polymorphism-358 Is Required for G at -420 to Confer the Highest Plasma Resistin in the General Japanese Population

Insulin resistance is a feature of type 2 diabetes. Resistin, secreted from adipocytes, causes insulin resistance in mice. We previously reported that the G/G genotype of single nucleotide polymorphism (SNP) at −420 (rs1862513) in the human resistin gene (RETN) increased susceptibility to type 2 diabetes by enhancing its promoter activity. Plasma resistin was highest in Japanese subjects with G/G genotype, followed by C/G, and C/C. In this study, we cross-sectionally analyzed plasma resistin and SNPs in the RETN region in 2,019 community-dwelling Japanese subjects. Plasma resistin was associated with SNP-638 (rs34861192), SNP-537 (rs34124816), SNP-420, SNP-358 (rs3219175), SNP+299 (rs3745367), and SNP+1263 (rs3745369) (P<10−13 in all cases). SNP-638, SNP -420, SNP-358, and SNP+157 were in the same linkage disequilibrium (LD) block. SNP-358 and SNP-638 were nearly in complete LD (r2 = 0.98), and were tightly correlated with SNP-420 (r2 = 0.50, and 0.51, respectively). The correlation between either SNP-358 (or SNP-638) or SNP-420 and plasma resistin appeared to be strong (risk alleles for high plasma resistin; A at SNP-358, r2 = 0.5224, P = 4.94×10−324; G at SNP-420, r2 = 0.2616, P = 1.71×10−133). In haplotypes determined by SNP-420 and SNP-358, the estimated frequencies for C-G, G-A, and G-G were 0.6700, 0.2005, and 0.1284, respectively, and C-A was rare (0.0011), suggesting that subjects with A at −358, generally had G at −420. This G-A haplotype conferred the highest plasma resistin (8.24 ng/ml difference/allele compared to C-G, P<0.0001). In THP-1 cells, the RETN promoter with the G-A haplotype showed the highest activity. Nuclear proteins specifically recognized one base difference at SNP-358, but not at SNP-638. Therefore, A at -358 is required for G at −420 to confer the highest plasma resistin in the general Japanese population. In Caucasians, the association between SNP-420 and plasma resistin is not strong, and A at −358 may not exist, suggesting that SNP-358 could explain this ethnic difference.

Characterization of a novel murine preadipocyte line, AP‐18, isolated from subcutaneous tissue: Analysis of adipocyte‐related gene expressions

Adipocyte lines are a useful tool for adipocyte research. Recently, a new preadipocyte line designated AP-18 was established from subcutaneous tissue of the C3H/He mouse. In this study, we further characterized AP-18 cells. Adipocyte differentiation was assessed by accumulation of fat droplets stained by Oil Red O. The expression of the preadipocyte- or adipocyte-specific genes and adipocytokine genes was analysed qualitatively by RT-PCR and quantitatively by real-time PCR in comparison with the LM cell, a murine fibroblast line, and the 3T3-L1 cell, respectively. AP-18 cells were fibroblastoid in maintenance culture. After the confluence, fat droplets were accumulated in 50-60% of the cells cultured in the medium alone and in 70-90% of the cells cultured with insulin within 2 to 3 weeks. The fat accumulation was not promoted by the addition of dexamethazone, IBMX (3-isobutyl-1-methylxanthine) or troglitazone in combination with insulin, which were obligatory for differentiation of the 3T3-L1 cell, a murine preadipocyte line. Throughout the differentiation, AP-18 cells expressed Pref-1, LPL, C/EBP beta, C/EBP delta, RXR alpha, C/EBP alpha, PPAR gamma, RXR gamma, aP2, GLUT4, SCD1, UCP2, UCP3, TNFalpha, resistin, leptin, adiponectin and PAI-1 genes, but not the UCP1 gene, indicating that the cell is derived from WAT (white adipose tissue). The time course of these gene expressions was similar to that of 3T3-L1 cells, although the expressions were slower and lower in AP-18 cells. These data indicate that AP-18 cells are preadipocytes originated from WAT and differentiate into adipocytes under more physiological conditions than 3T3-L1 cells. AP-18 may be useful in adipocyte research.

Is rs34861192 or rs1862513 a more promising variant for determining plasma resistin in an aged Japanese population?

Is rs34861192 or rs1862513 a more promising variant for determining plasma resistin in an aged Japanese population?

Insilico Methodolgy - Resistin Involved In Diabesity

In the present study, the role of several genes/proteins involved in the evolution of diabesity have been studied by several bioinformatics tools and software. Sequence and Phylogenetic Analysis was done using SDSC Biology workbench, a web based bioinformatics toolkit. Our bioinformatics analysis reports resistin gene as ominous link with diabesity. This bioinformatics study will be useful for future studies towards therapeutic inventions of diabesity. A multiple sequence alignment approach is used followed by construction of phylogenetic tree to compare the homology of functional proteins in one species and between other species. Sequences are analyzed to find mutations, evolutionary relationships, predicting structure, function and its abnormalities.

Resistin gene promoter region polymorphism and the risk of hypertrophic cardiomyopathy in patients

Resistin, a novel cytokine, is associated with an inflammatory process and is suggested to induce hypertrophy in rat cardiomyocytes. Resistin gene expression has not been investigated in patients with hypertrophic cardiomyopathy (HCM). This study investigates resistin levels in HCM patients and healthy controls and the molecular basis for the regulation of the resistin gene (RETN) in a Pakistani population. Patients with HCM (n = 105) and healthy individuals (n = 110) were enrolled in this investigation. Serum resistin levels were determined by enzyme-linked immunosorbent assay (ELISA). RETN genotyping was performed by polymerase chain reaction (PCR) and DNA sequencing. Our data showed a statistically significant increase in resistin levels from HCM patients compared with healthy subjects (6.3 +/- 2.7 ng/mL in patients vs 3.4 +/- 2.1 ng/mL in controls, P < 0.0001). The RETN -420 C > G polymorphism was significantly high in patients with HCM compared with the control group (P < 0.001). There was a significant difference between the C and G alleles from HCM cases and controls (odds ratio [OR] = 3.54, 95% confidence interval [CI] = 2.36-5.30, P < 0.0001). Logistic-regression analysis showed that the increased resistin levels, and the RETN-420 C > G polymorphism were significantly associated with HCM. Our data suggest that the elevated resistin levels and the RETN -420 C > G polymorphism may be associated with cardiac hypertrophy in the study population.

Plasma resistin concentration determined by common variants in the resistin gene and associated with metabolic traits in an aged Japanese population

Resistin is a cytokine derived from adipose tissue and is implicated in obesity-related insulin resistance and type 2 diabetes mellitus. Polymorphisms of the resistin gene (RETN) have been shown to affect the plasma resistin concentration. The aims of this study were to identify polymorphisms of RETN that influence plasma resistin concentration and to clarify the relation between plasma resistin level and metabolic disorders in an aged Japanese cohort. The study participants comprised 3133 individuals recruited to a population-based prospective cohort study (KING study). Plasma resistin concentration, BMI, abdominal circumference, blood pressure, fasting plasma glucose and serum insulin concentrations, HbA(1c) content and serum lipid profile were measured in all participants. The HOMA index of insulin resistance (HOMA-IR) was also calculated. Eleven polymorphisms of RETN were genotyped. A combination of ANOVA and multiple linear regression analysis in screening and large-scale subsets of the study population revealed that plasma resistin concentration was significantly associated with rs34861192 and rs3745368 polymorphisms of RETN. Multiple linear regression analysis with adjustment for age and sex also showed that the plasma resistin level was significantly associated with serum concentrations of HDL-cholesterol, triacylglycerol and insulin, as well as with BMI. Our results implicate the rs34861192 and rs3745368 polymorphisms of RETN as robust and independent determinants of plasma resistin concentration in the study population. In addition, plasma resistin level was associated with dyslipidaemia, serum insulin concentration and obesity. ClinicalTrials.gov NCT00262691.

C/EBPalpha and the corepressors CtBP1 and CtBP2 regulate repression of select visceral white adipose genes during induction of the brown phenotype in white adipocytes by peroxisome proliferator-activated receptor gamma agonists.

White adipose tissue (WAT) stores energy in the form of triglycerides, whereas brown tissue (BAT) expends energy, primarily by oxidizing lipids. WAT also secretes many cytokines and acute-phase proteins that contribute to insulin resistance in obese subjects. In this study, we have investigated the mechanisms by which activation of peroxisome proliferator-activated receptor gamma (PPARgamma) with synthetic agonists induces a brown phenotype in white adipocytes in vivo and in vitro. We demonstrate that this phenotypic conversion is characterized by repression of a set of white fat genes ("visceral white"), including the resistin, angiotensinogen, and chemerin genes, in addition to induction of brown-specific genes, such as Ucp-1. Importantly, the level of expression of the "visceral white" genes is high in mesenteric and gonadal WAT depots but low in the subcutaneous WAT depot and in BAT. Mutation of critical amino acids within helix 7 of the ligand-binding domain of PPARgamma prevents inhibition of visceral white gene expression by the synthetic agonists and therefore shows a direct role for PPARgamma in the repression process. Inhibition of the white adipocyte genes also depends on the expression of C/EBPalpha and the corepressors, carboxy-terminal binding proteins 1 and 2 (CtBP1/2). The data further show that repression of resistin and angiotensinogen expression involves recruitment of CtBP1/2, directed by C/EBPalpha, to the minimal promoter of the corresponding genes in response to the PPARgamma ligand. Developing strategies to enhance the brown phenotype in white adipocytes while reducing secretion of stress-related cytokines from visceral WAT is a means to combat obesity-associated disorders.

PPARγ Pro12Ala Pro/Pro and resistin SNP‐420 G/G genotypes are synergistically associated with plasma resistin in the Japanese general population

The Ala allele of the Pro12Ala polymorphism (rs1801282) of peroxisome proliferator-activated receptor gamma (PPARgamma) is protective against type 2 diabetes (T2DM). Resistin, secreted from adipocytes, causes insulin resistance in rodents. Resistin gene expression is reduced by the PPARgamma ligand. We previously reported that subjects with the G/G genotype of a resistin gene single nucleotide polymorphism (SNP) at -420 (rs1862513) had the highest circulating resistin levels, followed by C/G and C/C. The aim of this study was to determine the relationship among PPARgamma Pro12Ala polymorphism, resistin SNP-420, and plasma resistin. We cross-sectionally analysed 2077 community-dwelling subjects attending an annual medical check-up. Genotypes were determined by TaqMan analysis. Fasting plasma resistin was measured using ELISA. Plasma resistin appeared to be higher in subjects with the Pro/Pro genotype of PPARgamma than those with Pro/Ala and Ala/Ala genotypes (mean +/- SE, 11.6 +/- 0.2 vs. 10.4 +/- 0.5 microg/l). Multiple regression analysis, adjusted for age, gender, BMI, and resistin SNP-420, revealed that the Pro/Pro genotype was a positive predictor of plasma resistin (PPARgamma , Pro/Pro vs. Pro/Ala + Ala/Ala, unstandardized regression coefficient (beta) = 1.03, P = 0.0384). The effects of the Pro/Pro genotype of PPARgamma (Pro/Pro vs. Pro/Ala + Ala/Ala) and the G/G genotype of resistin SNP-420 (G/G vs. C/C) on plasma resistin were synergistic (beta = 4.76, P = 0.011). The PPARgamma Pro12Ala Pro/Pro and resistin SNP-420 G/G genotypes were synergistically associated with plasma resistin, when adjusted for age, gender, and BMI, in the Japanese general population.

Resistin Is More Abundant in Liver Than Adipose Tissue and Is Not Up-Regulated by Lipopolysaccharide

Resistin is an adipokine correlated with inflammatory markers and is predictive for cardiovascular diseases. There is evidence that serum resistin levels are elevated in obese patients; however, the role of resistin in insulin resistance and type 2 diabetes remains controversial. We addressed the question of whether inflammation may induce expression of resistin in organs involved in regulation of total body energy metabolism, such as liver and adipose tissue (AT). Human liver tissue, sc AT, and omentum were cultured in the absence/presence of lipopolysaccharide (LPS). The resistin and cytokine mRNA and protein expression levels were determined by real-time PCR, ELISA, and Multiplex Technology, respectively. The localization of resistin in human liver was analyzed by immunohistochemistry. Resistin gene and protein expression was significantly higher in liver than in AT. Exposure of human AT and liver tissue in culture to LPS did not alter resistin concentration; however, concentrations of IL-1beta, IL-6, and TNFalpha were significantly increased in these tissues. In liver, resistin colocalizes with markers for Kupffer cells, for a subset of endothelial and fibroblast-like cells. High level of resistin gene and protein expression in liver compared to AT implies that resistin should not be considered only as an adipokine in humans. LPS-induced inflammation does not affect resistin protein synthesis in human liver and AT. This suggests that elevated serum resistin levels are not indicative for inflammation of AT or liver in a manner similar to known inflammatory markers such as IL-1beta, IL-6, or TNFalpha.

Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians

Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the -420C>G putative gain-of-function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans. We examined the association of three resistin polymorphisms, -852A>G, -420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C-reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851). Resistin levels were higher, dose-dependently, with the -420G allele (CC 5.9 +/- 2.7 ng/ml, GC 6.5 +/- 4.0 ng/ml and GG 7.2 +/- 4.8 ng/ml, trend P = 0.04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1.07 (1.00-1.15), P < 0.05)]. The -852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor-receptor 2 (sol-TNFR2) levels in fully adjusted models [1.06 (95% CI 1.01-1.11), P = 0.01)]. The estimated resistin haplotype (GGT) was associated with sol-TNFR2 (P = 0.04) and the AGT haplotype was related to CRP (P = 0.04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores. Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5' variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.

Adipocyte-specific Expression of Murine Resistin Is Mediated by Synergism between Peroxisome Proliferator-activated Receptor γ and CCAAT/Enhancer-binding Proteins

Resistin antagonizes insulin action in mouse, making it a potential therapeutic target for treating metabolic diseases such as diabetes. To better understand how mouse resistin gene (Retn) expression is restricted to fat tissue, we identified an adipocyte-specific enhancer located approximately 8.8-kb upstream of the transcription start site. This region contains a binding site for the master adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARgamma), and binds endogenous PPARgamma together with its partner retinoid-X receptor alpha (RXRalpha). It also contains three binding sites for CCAAT/enhancer-binding protein (C/EBP), and is bound by endogenous C/EBPalpha and C/EBPbeta in adipocytes. Exogenous expression of PPARgamma/RXRalpha and C/EBPalpha in non-adipocyte cells synergistically drives robust expression from the enhancer. Although PPARgamma ligands repress Retn transcription in adipocytes, rosiglitazone paradoxically stimulates the enhancer activity, suggesting that the enhancer is not directly involved in negative regulation. Unlike expression of Retn in mouse, human resistin (RETN) is expressed primarily in macrophages. Interestingly, the region homologous to the mouse Retn enhancer in the human gene contains all three C/EBP elements, but is not conserved for the sequence bound by PPARgamma. Furthermore, it displays little or no binding by PPARgamma in vitro. Taken together, the data suggest that a composite enhancer binding both PPARgamma and C/EBP factors confers adipocyte-specific expression to Retn in mouse, and its absence from the human gene may explain the lack of adipocyte expression in humans.

Resistin-Like Molecule-β in Scleroderma-Associated Pulmonary Hypertension

Scleroderma is a systemic, mixed connective tissue disease that can impact the lungs through pulmonary fibrosis, vascular remodeling, and the development of pulmonary hypertension and right heart failure. Currently, little is known about the molecular mechanisms that drive this condition, but we have recently identified a novel gene product that is up-regulated in a murine model of hypoxia-induced pulmonary hypertension. This molecule, known as hypoxia-induced mitogenic factor (HIMF), is a member of the newly described resistin gene family. We have demonstrated that HIMF has mitogenic, angiogenic, vasoconstrictive, inflammatory, and chemokine-like properties, all of which are associated with vascular remodeling in the lung. Here, we demonstrate that the human homolog of HIMF, resistin-like molecule (RELM)-beta, is expressed in the lung tissue of patients with scleroderma-associated pulmonary hypertension and is up-regulated compared with normal control subjects. Immunofluorescence colocalization revealed that RELM-beta is expressed in the endothelium and vascular smooth muscle of remodeled vessels, as well as in plexiform lesions, macrophages, T cells, and myofibroblast-like cells. We also show that addition of recombinant RELM-beta induces proliferation and activation of ERK1/2 in primary cultured human pulmonary endothelial and smooth muscle cells. These results suggest that RELM-beta may be involved in the development of scleroderma-associated pulmonary hypertension.

Effects of resistin expression on glucose metabolism and hepatic insulin resistance

In order to observe the effect of increased serum resistin on glucose metabolism, insulin sensitivity, and hepatic insulin resistance (IR), mice were intravenously injected with recombinant adenovirus carrying the resistin gene (Adv-resistin-EGFP). Changes in hepatic glucose metabolism were observed using the Periodic Acid-Schiff method. Hepatic AMP-activated protein kinase (AMPK) activation was assessed by Western blot analysis, and glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was determined using real-time RT-PCR. Although no effect on fasting blood glucose was detected, increased fasting insulin levels, decreased glucose tolerance and insulin sensitivity, and reduced hepatic glycogen levels and AMPK activation were seen in the Adv-resistin-EGFP mice. Finally, elevated G6Pase and PEPCK mRNA expression levels were detected upon overexpression of resistin. Resistin may inhibit hepatic AMPK activity, which results in elevated expression of gluconeogenic enzymes thereby affecting glucose metabolism and leading to decreased glycogen storage that contributes to the development of hepatic IR.

Resistin gene variations are associated with the metabolic syndrome in Japanese men

Metabolic syndrome is defined as a cluster of risk factors for cardiovascular disease and is intimately related to insulin resistance. Resistin, a hormone secreted by adipocytes, may play an important role in communication between adiposity and insulin resistance. We investigated whether variations in the resistin gene associated with metabolic syndrome in a Japanese population. We analyzed five SNPs, two of which were located in the promoter region (-420C > G, -358G > A), two in intron 2 (+157C > T, +299G > A), and one in the 3'-untranslated region (3'UTR) (+1263G > C) across the resistin gene in 2968 residents from an urban Japanese cohort. The associations of SNPs and haplotypes with metabolic syndrome were analyzed. The GAC and CGC haplotypes (comprising -420C > G, -358G > A, and +157C > T) had opposite influences on metabolic syndrome susceptibility in men; the former was associated with an increased risk and the latter with a decreased risk. We also found that the -420G allele was significantly associated with an increased risk of metabolic syndrome and significantly correlated with high diastolic blood pressure, high HOMA-IR values, high serum triglyceride levels, low HDL-cholesterol levels and high serum levels of adiponectin. We identified a risk-conferring SNP and haplotype of the resistin gene for metabolic syndrome in a Japanese population. Our data suggested that resistin gene is a susceptibility gene for metabolic syndrome in Japanese men.

The contributions of resistin and adiponectin gene single nucleotide polymorphisms to the genetic risk for polycystic ovary syndrome in a Japanese population

Polycystic ovary syndrome (PCOS) is a heterogeneous group of disorders that occur fairly commonly in women of reproductive age and are characterized by a variety of clinical manifestations, including insulin resistance that is independent of obesity. Recent studies suggest that altered adipocytokine gene expression is closely associated with insulin resistance and that single nucleotide polymorphisms (SNPs) modulate the expression and/or function of these genes, thereby affecting insulin sensitivity. With that in mind, we investigated whether SNPs at position −420 of the resistin gene (RETN) and/or −11377 of the adiponectin gene (ADIPOQ) modulate the susceptibility to PCOS. We evaluated the genotypes of 117 women with PCOS and 380 healthy fertile controls and measured the index of insulin resistance and hormonal profiles in the PCOS women. The RETN−420G/G homozygous variant genotype occurred significantly more frequently among the PCOS group than among the control group (15.4% vs. 8.4%, p = 0.035). PCOS women with the RETN−420G/G genotype also showed significantly higher BMIs and greater insulin resistance than those with RETN−420 C/C or C/G genotypes. The ADIPOQ SNP at −11377 showed no association with PCOS. We conclude that the RETN G/G at −420 genotype is associated with PCOS in Japanese women.

A Pilot Study Suggests that the G/G Genotype of Resistin Single Nucleotide Polymorphism at -420 May Be an Independent Predictor of a Reduction in Fasting Plasma Glucose and Insulin Resistance by Pioglitazone in Type 2 Diabetes

The aim of this study was to determine the relation between the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 (rs1862513) and glycemic control by pioglitazone in type 2 diabetes. In Study 1, 121 type 2 diabetic patients were treated with pioglitazone (15 or 30 mg/day) for 12 weeks, in addition to previous medication. In Study 2, 63 patients who had been treated with pioglitazone for 12 weeks were examined retrospectively. In Study 1, multiple regression analysis revealed that the G/G but not C/G genotype was correlated with a reduction in fasting plasma glucose (FPG) and homeostasis model assessment of insulin resistance (HOMA-IR) compared to C/C. When adjusted for age, gender, and BMI, the G/G genotype was an independent factor for the reduction of FPG (P=0.020) and HOMA-IR (P =0.012). When studies 1 and 2 were combined by adjusting the studies, age, gender, and BMI, the reduction of HbA1c was correlated with the G/G genotype (beta=-0.511, P=0.044). Therefore, this pilot study suggests that the G/G genotype of resistin SNP -420 may be an independent predictor of the reduction of fasting plasma glucose and HOMA-IR by pioglitazone.