Adipokine Gene Research Articles

PS4 - 19. Expression of lipid genes, but not adipokine genes, in visceral adipose tissue is related to liver damage in obese individuals

Obesity increases the risk to develop liver steatosis, inflammation, and consequently severe liver damage. This risk is associated with an increased flow of lipids and signaling molecules (adipokines), secreted by adipose tissue, through the liver. However, the relevance of lipids and adipokines in this crosstalk between adipose tissue and liver in obesity-related liver pathology is largely unknown. Therefore we investigated to what extend the expression of genes involved in lipid metabolism and adipokine genes in visceral adipose tissue is correlated to liver pathology in obese individuals.

Location, location, location: Beneficial effects of autologous fat transplantation

Visceral adiposity is a risk factor for cardiovascular disorders, type 2 diabetes mellitus (T2D) and associated metabolic diseases. Sub-cutaneous fat is believed to be intrinsically different from visceral fat. To understand molecular mechanisms involved in metabolic advantages of fat transplantation, we studied a rat model of diet-induced adiposity. Adipokine genes (Adiponectin, Leptin, Resistin and Visfatin) were expressed at 10,000 to a million-fold lower in visceral fat depot as compared to peripheral (thigh/chest) fat depots. Interestingly, autologous transplantation of visceral fat to subcutaneous sites resulted in increased gene transcript abundance in the grafts by 3 weeks post-transplantation, indicating the impact of local (residence) factors influencing epigenetic memory. We show here that active transcriptional state of adipokine genes is linked with glucose mediated recruitment of enzymes that regulate histone methylation. Adipose depots have “residence memory” and autologous transplantation of visceral fat to sub-cutaneous sites offers metabolic advantage.

Adipose tissue‐derived adiponectin expression is significantly associated with increased post operative mortality in horses undergoing emergency abdominal surgery

Adipose tissue is an important source of inflammatory cytokines (adipokines) and adiposity has been identified as having a significant effect on human morbidity and mortality. Obesity is also an emerging welfare problem in the UK horse population, but the role that it plays in secondary diseases is unclear. To examine the expression of inflammation-related adipokine genes in retroperitoneal adipose tissue of horses undergoing emergency abdominal surgery and to explore associations with adiposity and post operative survival. Retroperitoneal adipose tissue samples were obtained from 76 horses undergoing emergency abdominal surgery. Real-time PCR was used to measure gene expression for leptin, adiponectin, tumour necrosis factor-alpha, macrophage chemoattractant protein-1, macrophage inhibitory factor, serum amyloid A, haptoglobin and interleukin-1. Multivariate patterns of adipokine expression were explored with principal component analysis (PCA), whilst univariable associations with post operative survival were tested in a Cox proportional hazards model. Leptin gene expression was higher in overweight and obese horses than in lean animals. Expression of mRNA encoding adiponectin mRNA in visceral adipose tissue was positively associated with increased post operative mortality (hazard ratio 1.31, 95% CI 1.05-1.65). However, PCA did not demonstrate multivariable patterns of adipokine gene expression from visceral adipose tissue associated with body mass index or with survival. In horses presented with acute intestinal disease, increased adiponectin gene expression from retroperitoneal adipose tissue is associated with an increased risk of mortality. Obesity assessed by BMI had no association with increased post operative mortality in horses with primary gastrointestinal disease. Further study is warranted on the expression and effects of adipokines, particularly adiponectin, and correlation with postoperative outcome.

Differential effects of 1α,25-dihydroxycholecalciferol on MCP-1 and adiponectin production in human white adipocytes

Obesity is characterized by a low-grade inflammation in white adipose tissue (WAT), which promotes insulin resistance. Low serum levels of 1α,25-dihydroxycholecalciferol (DHCC) associate with insulin resistance and higher body mass index although it is unclear whether vitamin D supplementation improves insulin sensitivity. We investigated the effects of DHCC on adipokine gene expression and secretion in adipocytes focusing on two key factors with pro-inflammatory [monocyte chemoattractant protein-1 (MCP-1/CCL2)] and anti-inflammatory [adiponectin (ADIPOQ)] effects. Pre-adipocytes were isolated from human subcutaneous WAT and cultured until full differentiation. Differentiated adipocytes were either pre-treated with DHCC (10(-7) M) and subsequently incubated with tumor necrosis factor-α (TNFα, 100ng/mL) or concomitantly incubated with TNFα/DHCC. MCP1 and adiponectin mRNA expression was measured by RT-PCR and protein release by ELISA. DHCC was not toxic and did not affect adipocyte morphology or the mRNA levels of adipocyte-specific genes. TNFα induced a significant increase in CCL2 mRNA and protein secretion, while DHCC alone reduced CCL2 mRNA expression (~25%, p<0.05). DHCC attenuated TNFα-induced CCL2 mRNA expression in both pre-incubation (~15%, p<0.05) and concomitant (~60%, p<0.01) treatments. TNFα reduced ADIPOQ mRNA (~80%) and secretion (~35%). DHCC alone decreased adiponectin secretion to a similar degree (~35%, p<0.05). Concomitant treatment with DHCC/TNFα for 48h had an additive effect, resulting in a pronounced reduction in adiponectin secretion (~70%). DHCC attenuates MCP-1 and adiponectin production in human adipocytes, thereby reducing the expression of both pro- and anti-inflammatory factors. These effects may explain the difficulties so far in determining the role of DHCC in insulin sensitivity and obesity in humans.

Mechanistic Modeling of the Effects of Glucocorticoids and Circadian Rhythms on Adipokine Expression

A mechanism-based model was developed to describe the effects of methylprednisolone (MPL), circadian rhythms, and the glucose/free fatty acid (FFA)/insulin system on leptin and adiponectin expression in white adipose tissue in rats. Fifty-four normal Wistar rats received 50 mg/kg MPL intramuscularly and were sacrificed at various times. An additional set of 54 normal Wistar rats were sacrificed at 18 time points across the 24-h light/dark cycle and served as controls. Measurements included plasma MPL, glucocorticoid receptor (GR) mRNA, leptin mRNA, adiponectin mRNA, plasma leptin, adiponectin, glucose, FFA, and insulin. MPL pharmacokinetics was described by a two-compartment model with two absorption components. All measured plasma markers and mRNA expression exhibited circadian patterns except for adiponectin and were described by Fourier harmonic functions. MPL caused significant down-regulation in GR mRNA with the nadir occurring at 5 h. MPL disrupted the circadian patterns in plasma glucose and FFA by stimulating their production. Plasma glucose and FFA subsequently caused an increase in plasma insulin. Furthermore, MPL disrupted the circadian patterns in leptin mRNA expression by stimulating its production. This rise was closely followed by an increase in plasma leptin. Both leptin mRNA and plasma leptin peaked at 12 h after MPL and eventually returned back to their circadian baselines. MPL and insulin had opposing effects on adiponectin mRNA expression and plasma adiponectin, which resulted in biphasic pharmacodynamic profiles. This small systems model quantitatively describes, integrates, and provides additional insights into various factors controlling adipokine gene expression.

Comment on: Kim et al. (2010) Hypothalamic Angptl4/Fiaf Is a Novel Regulator of Food Intake and Body Weight. Diabetes;59:2772–2780

The article by Kim et al. (1) outlines a detailed series of experiments that purport to establish angiopoietin-like protein 4(Angptl4)/fasting- induced adipose factor (Fiaf) as a novel hypothalamic regulator of food intake and body weight in the mouse. Although the results of this study are impressive, we note that all previous publications on the regulation of fiaf in the murine brain were overlooked. For example, in our ongoing studies of adipokine gene expression in the nervous …

Fructose alters adiponectin, haptoglobin and angiotensinogen gene expression in 3T3-L1 adipocytes

Fructose- or sucrose-rich diets can cause insulin resistance and increase the risk of cardiovascular disease. Adipokines are correlated with the development of these diseases in obesity. We hypothesize that fructose and sucrose induce insulin resistance via effects on adipokine gene expression in adipocytes. This study analyzed the effect of fructose or glucose on adiponectin, haptoglobin, and angiotensinogen gene expression in 3T3-L1 adipocytes. Ten days after differentiation, the cells were pretreated with serum- and glucose-free medium. Twenty-four hours later, fructose or glucose (0, 5, 10, or 20 mmol) was added into the medium, and the cells were collected after a further 24 hours. Adiponectin, haptoglobin, and angiotensinogen gene expression were determined. Adiponectin gene expression increased when 10 or 20 mmol glucose was added compared with that observed for the non-hexose-treated cells. A similar effect occurred when 5 mmol fructose was added. Glucose (10 mmol) and fructose (20 mmol) stimulated haptoglobin gene expression in 3T3-L1 adipocytes compared with 0 mmol, with glucose producing a more pronounced effect. Although 20 mmol fructose caused an increase in angiotensinogen gene expression, glucose did not. In conclusion, in this study of 2 hexoses revealed an increase in adiponectin gene expression, suggesting that the effect of a glucose-rich diet on the development of insulin resistance is not related to the effect of these hexoses on adipocyte adiponectin gene expression. However, insulin resistance and cardiovascular disease promoted by fructose-rich diets could be partially related to the effect of fructose on adiponectin and angiotensinogen gene expression.

Regulation of adipokine secretion byn-3 fatty acids

Obesity leads to several chronic morbidities including type 2 diabetes, dyslipidaemia, atherosclerosis and hypertension, which are major components of the metabolic syndrome. White adipose tissue (WAT) metabolism and WAT-derived factors (fatty acids and adipokines) play an important role in the development of these metabolic disturbances. In fact, dysregulated adipokine secretion from the expanded WAT of obese individuals contributes to the development of systemic low-grade inflammation, insulin resistance and metabolic syndrome. The n-3 PUFA EPA and DHA have been widely reported to have protective effects in a range of chronic inflammatory conditions including obesity. In fact, n-3 PUFA have been shown to ameliorate low-grade inflammation in adipose tissue associated with obesity and up-regulate mitochondrial biogenesis and induce beta-oxidation in WAT in mice. Moreover, the ability of n-3 PUFA to regulate adipokine gene expression and secretion has been observed both in vitro and in vivo in rodents and human subjects. The present article reviews: (1) the physiological role of adiponectin, leptin and pre-B cell colony-enhancer factor/visfatin, three adipokines with immune-modulatory properties involved in the regulation of metabolism and insulin sensitivity and (2) the actions of n-3 PUFA on these adipokines focusing on the underlying mechanisms and the potential relationship with the beneficial effects of these fatty acids on obesity-associated metabolic disorders. It can be concluded that the ability of n-3 PUFA to improve obesity and insulin resistance conditions partially results from the modulation of WAT metabolism and the secretion of bioactive adipokines including leptin, adiponectin and visfatin.

Tissue-specific effects of valsartan onrstnandfiafgene expression in theob/obmouse

The RAS is a novel target in the study of diabetes, and clinical trials have indicated that ARBs, such as valsartan, may exert some of their clinical effects through an influence on adipose tissue. We studied the effect of valsartan on adipokine genes resistin (rstn) and fasting-induced adipose factor (fiaf) using obese and diabetic ob/ob mice. In addition to visceral and subcutaneous fat, rstn and fiaf mRNA levels were also measured in several other tissues known to express these adipokines, including the pituitary, cerebral cortex and hypothalamus. The significant findings were that (a) fiaf gene expression was elevated two- to fourfold in visceral and subcutaneous fat from ob/ob mice, compared with lean controls; (b) the increase in fiaf mRNA in subcutaneous, but not visceral, fat from ob/ob mice was returned to lean control levels following 2 weeks of valsartan treatment; (c) fiaf expression was reduced in the hypothalamus, but not in the cortex or pituitary, of ob/ob mice; (d) rstn expression was greatly reduced in visceral fat from ob/ob mice, compared with lean controls, but this was unaffected by valsartan; and (e) rstn expression was unchanged in all other tissues from ob/ob mice, with or without valsartan treatment.

Cold-induced alteration of adipokine profile in humans

Adipose tissue function and sympathetic nervous system (SNS) activity are tightly interconnected. Adipose tissue is densely innervated by the SNS. Adipokines secreted by adipose tissue are implicated in maintaining energy homeostasis, the control of blood pressure, immune system function, hemostasis, and atherosclerosis. Little is known about a direct effect of SNS activation on influencing adipose tissue endocrine function in humans. In 10 lean, healthy male volunteers, SNS was activated by whole-body exposure to cold for 2 hours; a group of 10 subjects served as controls. Vital parameters were evaluated, plasma adipokine levels were measured, and adipokine gene expression in subcutaneous abdominal adipose tissue was determined. Cold exposure caused an increase in cold sensation and a drop in body temperature and heart rate. Norepinephrine, but not epinephrine, plasma levels were elevated. Adiponectin plasma concentrations were acutely and significantly decreased. There was a trend of increased monocyte chemoattractant protein–1 plasma concentrations. Interleukin-6 and leptin levels increased and decreased, respectively, in both groups. Vascular endothelial growth factor plasma levels were unaffected. Subcutaneous adipokine gene expression was unchanged. Cold exposure caused SNS activation and differentially influenced adipokine secretion. Adiponectin levels were acutely reduced, whereas monocyte chemoattractant protein–1 concentrations tended to increase. No specific changes in leptin and IL-6 concentrations were detectable. The observed alterations appeared to be posttranscriptional because adipokine gene expression was found to be unaltered.

Expression of inflammatory molecules and associations with BMI in children

Adipose tissue secrets several adipokines that have been proposed to be enrolled in many inflammatory pathways. Our aim was to investigate the adipokine expression in adipose tissue and peripheral blood mononuclear cells (PBMCs) in children. Thirty-one (17 males and 14 females) healthy children aged 10.9 +/- 1.8 years with a body mass index (BMI) of 19.3 +/- 3.5 kg m(-2) were enrolled. Adipokines (TNF-alpha, IL-6 and leptin) gene expression was quantified by real-time quantitative PCR in adipose tissue and PBMCs from the same children. Their serum levels were also measured. BMI was positively correlated with leptin gene expression in adipose tissue and with leptin serum levels (beta = 0.476, P = 0.006 and beta = 0.576, P = 0.003 respectively). Leptin's serum levels were positively correlated with leptin gene expression in adipose tissue (beta = 0.462, P = 0.02). Adipose tissue gene expression of leptin and TNF-alpha and serum leptin and TNF-alpha serum levels were positively correlated (beta = 0.752, P < 0.001, beta = 0.311 and P = 0.015 respectively). In PBMCs, a positive correlation between TNF-alpha and IL-6 expression was found (beta = 0.526, P = 0.042). We demonstrated powerful correlations of adipokines gene expression in adipose tissue and PBMCs in children, underlying that these molecules share common pathways related to childhood obesity.

Resveratrol modulates adipokine expression and improves insulin sensitivity in adipocytes: Relative to inhibition of inflammatory responses

Resveratrol is a potent inhibitor of inflammation and has anti-diabetic potentiality, however whether its anti-inflammatory potency contributes to the amelioration of diabetes or insulin resistance remains to be determined. This study aims at evaluating the effects of resveratrol on inflammation-related adipokines expression and insulin sensitivity in adipocytes. We stimulated RAW264.7 cells with LPS and collected the supernatant as a conditioned medium (CM) for the culture of adipocytes. Resveratrol, at concentrations ranging from 0.1 to 10 μM, effectively inhibited lipopolysaccharide (LPS)-induced TNF-α and IL-6 production with the downregulation of relative genes expression in macrophages. Exposing differentiated 3T3-L1 cells to RAW264.7 CM resulted in gene over-expressions of TNF-α, IL-6 and resistin, however, mRNA expression of adiponectin and PPARγ were down-regulated. Pretreatment of CM from resveratrol-treated macrophages reduced the elevated levels of TNF-α and IL-6, and significantly reversed inflammation-related changes in adipokine gene expression in 3T3-L1 adipocytes. Resveratrol suppressed extracellular receptor-activated kinase (ERK) and transcription factor-κB (NF-κB) activation by reducing the phosphorylation of ERK1/2 and NF-κB p65; moreover, it modulated insulin signaling transduction by modification of Ser/Thr phosphorylation of insulin receptor substrate-1 (IRS-1) and downstream AKT (T308), and thereby improved insulin sensitivity in adiposities. These results demonstrated that resveratrol modulated adipokines expression and improved insulin sensitivity which relative to inhibition of inflammatory-like response in adipocytes.

Circulating and Adipose Tissue Gene Expression of Zinc-α2-Glycoprotein in Obesity: Its Relationship with Adipokine and Lipolytic Gene Markers in Subcutaneous and Visceral Fat

Zinc-alpha2-glycoprotein (ZAG) is a soluble protein similar to the class I major histocompatibility complex heavy chain, which has been implicated in lipid catabolism. We hypothesized that ZAG mRNA expression in adipose tissue may be linked with lipolytic and adipokine gene expression and have a close relationship with clinical phenotype. The objective of the study was to analyze ZAG gene expression in human adipose tissue from lean and obese subjects. ZAG circulating plasma levels and its relationship with cardiometabolic risk factors were also studied. Seventy-three Caucasian (43 male and 30 female) subjects were included. Plasma and adipose tissue [sc (SAT) and visceral (VAT)] from the same patient were studied. mRNA of PPARgamma, hormone-sensitive lipase (HSL), adipose triglyceride lipase, adiponectin, omentin, visfatin, and ZAG were quantified. Plasma concentrations of ZAG were determined with ELISA. ZAG plasma levels showed a negative correlation with insulin (r = -0.39; P = 0.008) and the homeostasis model assessment for insulin resistance index (r = -0.36; P = 0.016). No differences in ZAG circulating levels according to body mass index classification were observed. ZAG expression in SAT was significantly reduced in overweight and obese individuals compared with lean subjects (P < 0.001 and P = 0.007, respectively). ZAG mRNA expression in both SAT and VAT depots were negatively correlated with many clinical and metabolic cardiovascular risk factors. After multiple linear regression analysis, SAT ZAG was mainly predicted by adiponectin mRNA expression (B = 0.993; P < 0.0001) and plasma triglyceride levels (B = -0.565; P = 0.006). VAT ZAG expression was predicted by adiponectin expression (B = 0.449; P < 0.0001), and HSL VAT expression (B = 0.180; P = 0.023). The present study provides evidence of a role of ZAG gene in adipose tissue metabolism, with a close association with adiponectin gene expression in sc and visceral fat.

Adipokine gene transcription level in adipose tissue of runt piglets

Runt piglets were used as a model for neonatal stress to test the hypothesis that stress during the pre-weaning period can alter adipokine gene transcription levels. Runts were selected by birth mass <1kg and compared to littermates (controls) of mean litter weight. Subcutaneous (SQ) and perirenal (PR) adipose tissues were collected at d1 (n=5), d7 (n=7) or d21 (n=9) of age. Real time PCR was used to quantify mRNA abundance for: leptin, adiponectin, interleukin 1beta (IL1beta), IL6, IL8, IL10, IL15, tumor necrosis factor alpha, haptoglobin, macrophage migration inhibitory factor (MIF), monocyte chemotactic protein, vascular endothelial growth factor and cyclophilin. Leptin and adiponectin mRNA abundance were lower, while IL1beta, IL6, IL10 and MIF mRNA abundance were higher in SQ of runts than controls at d1 (P<0.05). Leptin, IL6, IL10, haptoglobin and MIF mRNA abundance were higher in PR from runts than controls at d7 (P<0.05) and MIF mRNA abundance was elevated by 30 fold in PR of runts at d21 (P<0.001). Thus, stressors affecting neonatal runts produce different responses in adipokine gene transcription by PR and SQ than in normal sized littermates.

Genetic variation in adipokine genes and risk of colorectal cancer

Genetic variation in adipokine genes and risk of colorectal cancer

Grape-seed procyanidins modulate inflammation on human differentiated adipocytes in vitro

Flavonoids are functional constituents of many fruits and vegetables. Procyanidins are flavonoids with an oligomeric structure, and it has been shown that they can improve the pathological oxidative state of a diabetic situation. To evaluate whether procyanidins can modulate inflammation, an event strongly associated with obesity, diabetes and insulin resistance states, we used human adipocytes (SGBS) and macrophage-like (THP-1) cell lines and administered an extract of grape-seed procyanidins (GSPE). THP-1 and SGBS cells pre-treated with GSPE showed a reduction of IL-6 and MCP-1 expression after an inflammatory stimulus. GSPE stimuli alone modulate adipokine ( APM1 and LEP) and cytokine ( IL-6 and MCP-1) gene expression. GSPE partially inhibited NF-κB translocation to the nucleus in both cell lines. These preliminary findings demonstrate that GSPE reduces the expression of IL-6 and MCP-1 and enhances the production of the anti-inflammatory adipokine adiponectin suggesting that may have a beneficial effect on low-grade inflammatory diseases such obesity and type 2 diabetes.

Genetic variation in adipokine genes and risk of colorectal cancer

Obesity has been related to an increased risk of colorectal cancer (CRC). Adipokines produced by the adipose tissue are directly linked to obesity and may thus contribute to the pathogenesis of CRC. We hypothesized that potentially functional polymorphisms in the adipokine genes leptin (LEP), leptin receptor (LEPR), resistin (RETN), and adiponectin (ADIPOQ) may be associated with CRC. We studied the association of four putatively functional single nucleotide polymorphisms (SNPs) with CRC risk using a hospital-based study design with 702 cases and 752 controls from the Czech Republic. We used likelihood ratio tests to select the best model to represent the relationship between genotypes and risk of CRC. Age-adjusted odds ratios (ORs) under the best model were calculated for each SNP. Previous genotyping data on insulin (INS)-related genes were used to explore interactions between genes in obesity- and diabetes-related pathways by using two independent methods, logistic regression, and multifactor-dimensionality reduction. A trend to associate between the RETN SNP rs1862513 (C-420G) and CRC risk was observed (per allele OR 1.18, 95% confidence interval (0.99-1.40). Statistically, significant interactions were observed between the INS SNP rs3842754 (+1127INSPstI) genotypes and both the LEPR SNP rs1137101 (Q223R) and the ADIPOQ SNP rs266729 (C-11374G) genotypes. Our results suggest that variants in the adipokine genes may affect CRC risk in combination with variants in diabetes-related genes.

Lipopolysaccharide (LPS) stimulates adipokine and socs3 gene expression in mouse brain and pituitary gland in vivo, and in N-1 hypothalamic neurons in vitro

Adipokines that modulate metabolic and inflammatory responses, such as resistin ( rstn) and fasting-induced adipose factor ( fiaf), are also expressed in mouse brain and pituitary gland. Since lipopolysaccharide (LPS)-induced endotoxinemia provokes an anorectic response via a hypothalamic-dependent mechanism we hypothesized that LPS would also modify hypothalamic adipokine expression. Challenging male CD-1 mice with LPS (5 mg/kg; s.c.) significantly reduced bodyweight (24 h) and realtime RT-PCR revealed time- and tissue-dependent increases in rstn, fiaf and suppressor of cytokine signaling-3 ( socs-3) mRNA in hypothalamic, pituitary, cortical and adipose tissues. Gene expression was rapidly increased (3–6 h) in the hypothalamus and pituitary, but returned to normal within 24 h. In contrast, with the exception of rstn in fat, the expression of target genes remained elevated in cortex and visceral fat at 24 h post-injection. In order to more specifically examine the hypothalamic response to LPS we investigated its effects directly on N-1 hypothalamic neurons in vitro. LPS (25 μg/mL; 3 h) had no effect on rstn mRNA, but significantly stimulated fiaf and socs-3 expression. Although various toll-like receptor 4 (TLR4) antagonists (parthenolide, PD098059, and SB202190) did not prevent the LPS-induced increases in fiaf and socs-3, they did partially attenuate its stimulatory effects. We conclude that LPS treatment increases the expression of central, and possibly neuronal, adipokine genes which may influence local tissue repair and function, but could also have downstream consequences on the hypothalamic control of appetite and energy metabolism following an inflammatory insult.

Coadministration of Coenzyme Q prevents Rosiglitazone-induced adipogenesis in ob/ob mice

The aim of this study is to determine the effect of coenzyme Q (Q) on ob/ob mice treated or not with thiazolidinedione (TZD). Ob/ob mice were treated with Q, Rosiglitazone or a combination of both molecules for 13 days; physical and metabolic parameters as well as oral glucose tolerance test were assessed. mRNA expression of genes of energy dissipation and storage were measured by real-time PCR. Q treatment improved some metabolic parameters in ob/ob mice. Surprisingly, cotreatment with Rosiglitazone and Q improved metabolic parameters and prevented TZD increase in body weight and adiposity, mainly by increasing lipid oxidation in adipose tissue, reducing lipid synthesis and balancing adipokine gene expression. Our finding suggests that Rosiglitazone and coenzyme Q bitherapy could prevent the body weight gain associated with adipogenesis and could improve the clinical use of these compounds.

Adipokine genes and prostate cancer risk

Adiposity and adipocyte-derived cytokines have been implicated in prostate carcinogenesis. However, the relationship of adipokine gene variants with prostate cancer risk has not been thoroughly investigated. We therefore examined common variants of the IL6, LEP, LEPR, TNF and ADIPOQ genes in relation to prostate cancer in a case-control study nested within a large cohort of Finnish men. The study sample consisted of 1,053 cases of prostate cancer, diagnosed over an average 11 years of follow up, and 1,053 controls matched to the cases on age, intervention group and date of baseline blood draw. Logistic regression was used to model the relative odds of prostate cancer. We also examined genotypes in relation to serum insulin, IGF-1 and IGF-1:IGFBP-3 among 196 controls. Variant alleles at three loci (-14858A>G, -13973A>C, -13736C>A) in a potential regulatory region of the LEP gene conferred a statistically significant 20% reduced risk of prostate cancer. For example, at the -14858A>G locus, heterozygotes and homozygotes for the A allele had an odds ratio (OR) of prostate cancer of 0.76 [95% confidence interval (CI) 0.62, 0.93] and 0.79 (95% CI 0.60, 1.04), respectively. At 13288G>A, relative to the GG genotype, the AA genotype was associated with a suggestive increased risk of prostate cancer (OR = 1.29; 95% CI 0.99,1.67; p(trend) = 0.05). Polymorphisms in the IL6, LEPR, TNF and ADIPOQ genes were not associated with prostate cancer. Allelic variants in the LEP gene are related to prostate cancer risk, supporting a role for leptin in prostate carcinogenesis.