FFAs and adipokine-mediated regulation of hsa-miR-143 expression in human adipocytes

Accumulating evidence suggests that microRNAs (miRNAs) play an important role in regulating the pathways in adipose tissue that control processes such as adipogenesis, insulin resistance, and inflammation. MiR-143 is a well-characterized miRNA involved in adipogenesis and may be involved in regulating insulin resistance. Free fatty acids (FFAs) and adipokines, such as tumor necrosis factor-α (TNF-α), leptin, resistin, and interleukin-6 (IL-6), have already been identified as main regulators of obesity and insulin sensitivity. Therefore, we studied the effects of these inflammatory cytokines on the expression of miR-143. FFAs, resistin, and leptin downregulated miR-143 expression in human adipocytes, whereas TNF-α and IL-6 had little effect on miR-143 expression. These results suggest that the expression of miR-143 is affected by a variety of factors that are related to insulin sensitivity. Therefore, miR-143 may be an important mediator in the development of obesity-related insulin resistance.     

TNF-α, IL-6, and Leptin Increase the Expression of miR-378, an Adipogenesis-Related microRNA in Human Adipocytes

Obesity has become a global public health problem associated with complications including type 2 diabetes, cardiovascular disease, and several cancers. Adipocyte differentiation (adipogenesis) plays an important role in obesity and energy homeostasis. Adipose tissue secretes multiple cytokines and adipokines which can cause the complications of obesity, especially insulin resistance. TNF-α, IL-6, leptin, and resistin have been identified as the main regulators of obesity and insulin activity. miR-378 is highly induced during adipogenesis and has been reported to be positively regulated in adipogenesis. In the current study, matured human adipocytes were treated with TNF-α, IL-6, leptin, or resistin on the 15th day after the induction of human pre-adipocyte differentiation. We demonstrated that TNF-α, IL-6, and leptin upregulated miR-378 expression indicating that miR-378 probably is a novel mediator in the development of insulin resistance related to obesity.     

Hypoxia and the endocrine and signalling role of white adipose tissue

White adipose tissue is a major endocrine and signalling organ. It secretes multiple protein hormones and factors, termed adipokines (such as adiponectin, leptin, IL-6, MCP-1, TNFalpha) which engage in extensive cross-talk within adipose tissue and with other tissues. Many adipokines are linked to inflammation and immunity and these include cytokines, chemokines and acute phase proteins. In obesity, adipose tissue exhibits a major inflammatory response with increased production of inflammation-related adipokines. It has been proposed that hypoxia may underlie the inflammatory response in adipose tissue and evidence that the tissue is hypoxic in obesity has been obtained in animal models. Cell culture studies have demonstrated that the expression and secretion of key adipokines, including leptin, IL-6 and VEGF, are stimulated by hypoxia, while adiponectin (with an anti-inflammatory action) production falls. Hypoxia also stimulates glucose transport by adipocytes and may have a pervasive effect on cell function within adipose tissue.     

Polyphenol-rich green tea extract improves adipose tissue metabolism by down-regulating miR-335 expression and mitigating insulin resistance and inflammation

Obesity leads to changes in miRNA expression in adipose tissue, and this modulation is linked to the pathophysiology of the disease. Green tea (GT) is a natural source of polyphenols that have been shown to confer health benefits, particularly preventing metabolic diseases. Here, we investigated if the beneficial effects of GT in obesity results from changes in the miRNA profile in white adipose tissue. GT treatment [500 mg/body weight (BW)/12 weeks] increased energy expenditure of high-fat diet-fed mice (16 weeks), leading to reduced weight gain, decreased adiposity, reduced inflammation and improved insulin sensitivity. These phenotypes were associated with a decrease in the expression of miR-335 in the adipose tissue. miR-335 was up-regulated by TNF-α in adipocytes and, in turn, down-regulated genes involved in insulin signaling and lipid metabolism. On the other hand, GT inhibited TNF-α effect. In conclusion, miR-335 serves as a link between inflammation and impaired metabolism in adipose tissue, providing an important mechanistic insight into the molecular basis underlying GT action during obesity.     

Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: a cross-sectional study

The goal of the study was to determine the association between diabetes and inflammation in clinically diagnosed diabetes patients. We hypothesized that low-grade inflammation in diabetes is associated with the level of glucose control. Using a cross-sectional design we compared pro- and anti-inflammatory cytokines in a community-recruited cohort of 367 Mexican Americans with type 2-diabetes having a wide range of blood glucose levels. Cytokines (IL-6, TNF-α, IL-1β, IL-8) and adipokines (adiponectin, resistin and leptin) were measured using multiplex ELISA. Our data indicated that diabetes as whole was strongly associated with elevated levels of IL-6, leptin, CRP and TNF-α, whereas worsening of glucose control was positively and linearly associated with high levels of IL-6, and leptin. The associations remained statistically significant even after controlling for BMI and age (p = 0.01). The association between TNF-α, however, was attenuated when comparisons were performed based on glucose control. Strong interaction effects between age and diabetes and BMI and diabetes were observed for IL-8, resistin and CRP. The cytokine/adipokine profiles of Mexican Americans with diabetes suggest an association between low-grade inflammation and quality of glucose control. Unique to in our population is that the chronic inflammation is accompanied by lower levels of leptin.     

Effects of 17β-estradiol and progesterone on the production of adipokines in differentiating 3T3-L1 adipocytes: Role of Rho-kinase

Effect of female sex hormones on the production/release of adipocyte-derived cytokines has been debatable. Furthermore, whether the cellular signaling triggered by these hormones involve Rho-kinase has not been investigated yet. Therefore, in this study, effects of 17β-estradiol and progesterone as well as the Rho-kinase inhibitor, Y-27632 on the level of adipokines such as resistin, adiponectin, leptin, TNF-α and IL-6 were investigated in 3T3-L1-derived adipocytes. Differentiation was induced in the post-confluent preadipocytes by the standard differentiation medium (Dulbecco’s modified Eagle’s medium with 10% fetal bovine serum together with the mixture of isobutylmethylxanthine, dexamethasone and insulin) in the presence of 17β-estradiol (10⁻⁸–10⁻⁷ M), progesterone (10⁻⁶–10⁻⁵ M), the Rho-kinase inhibitor, Y-27632 (10⁻⁵ M) and their combination for 8 days. Measurements of the adipokines were performed in the culturing medium by ELISA kits using specific monoclonal antibodies. 17β-estradiol elevated resistin but decreased adiponectin and IL-6 levels; however, it did not alter the concentration of leptin and TNF-α. Y-27632 pretreatment inhibited the rise of resistin and the fall of adiponectin by 17β-estradiol without any effects by its own. Progesterone did not change resistin, leptin and TNF-α level; however, it elevated adiponectin and decreased IL-6 production. Neither 17β-estradiol nor Y-27632 was able to antagonize the increase of adiponectin and the reduction of IL-6 levels by progesterone. While Y-27632 alone lowered IL-6 level, it increased leptin and TNF-α concentration without altering resistin and adiponectin. In conclusion, 17β-estradiol could modify adipokine production in 3T3-L1 adipocytes with the actions some of which involve Rho-kinase mediation.     

Inflammation and metabolic dysfunction: links to cardiovascular diseases

Abdominal obesity is a major risk factor for cardiovascular disease, and recent studies highlight a key role of adipose tissue dysfunction, inflammation, and aberrant adipokine release in this process. An increased demand for lipid storage results in both hyperplasia and hypertrophy, finally leading to chronic inflammation, hypoxia, and a phenotypic change of the cellular components of adipose tissue, collectively leading to a substantially altered secretory output of adipose tissue. In this review we have assessed the adipo-vascular axis, and an overview of adipokines associated with cardiovascular disease is provided. This resulted in a first list of more than 30 adipokines. A deeper analysis only considered adipokines that have been reported to impact on inflammation and NF-κB activation in the vasculature. Out of these, the most prominent link to cardiovascular disease was found for leptin, TNF-α, adipocyte fatty acid-binding protein, interleukins, and several novel adipokines such as lipocalin-2 and pigment epithelium-derived factor. Future work will need to address the potential role of these molecules as biomarkers and/or drug targets.     

The Roles of Adipokines,Proinflammatory Cytokines,and Adipose Tissue Macrophages in Obesity-Associated Insulin Resistance in Modest Obesity and Early Metabolic Dysfunction

The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.     

Benefits of Regular Exercise on Inflammatory and Cardiovascular Risk Markers in Normal Weight,Overweight and Obese Adults

Obesity is a worldwide epidemic that increases the risk of several well-known co-morbidities. There is a complicated relationship between adipokines and low-grade inflammation in obesity and cardiovascular disease (CVD). Physical activity practices have beneficial health effects on obesity and related disorders such as hypertension and dyslipidemia. We investigated the effects of 6 and 12 months of moderate physical training on the levels of adipokines and CVD markers in normal weight, overweight and obese volunteers. The 143 participants were followed up at baseline and after six and twelfth months of moderate regular exercise, 2 times a week, for 12 months. The volunteers were distributed into 3 groups: Normal Weight Group (NWG,), Overweight Group (OVG) and Obese Group (OBG). We evaluated blood pressure, resting heart rate, anthropometric parameters, body composition, fitness capacity (VO_2max and isometric back strength), cardiovascular markers (CRP, total cholesterol, LDL-c, HDL-c, homocysteine) and adipokine levels (leptin, adiponectin, resistin, IL-6 and TNF-alpha). There were no significant changes in anthropometric parameters and body composition in any of the groups following 6 and 12 months of exercise training. Leptin, IL-6 levels and systolic blood pressure were significantly elevated in OBG before the training. Regular exercise decreased HDL-c, leptin, adiponectin and resistin levels and diastolic blood pressure in OVG. In OBG, exercise diminished HDL-c, homocysteine, leptin, resistin, IL-6, adiponectin. Moderate exercise had no effect on the body composition; however, exercise did promote beneficial effects on the low-grade inflammatory state and CVD clinical markers in overweight and obese individuals.     

Adipokines and the cardiovascular system: mechanisms mediating health and disease

This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.     

Adiponectin: A biomarker for rheumatoid arthritis?

Recent achievements in the biology and the function of adipose tissue have regarded white adipose tissue (WAT) as an important endocrine and secretory organ. Releasing a series of multiple-function mediators, WAT is involved in a wide spectrum of diseases, including not only cardiovascular and metabolic complications, such as atherosclerosis and type 2 diabetes, but also inflammatory- and immune-related disorders, such as rheumatoid arthritis (RA) and osteoarthritis (OA). A large number of these mediators, called adipokines, such as tumor necrosis factor alpha (TNF-α), leptin, adiponectin, resistin, chemerin, interleukin-6 (IL-6), visfatin, and so on have been identified and studied widely. Important advances related to these proteins shed new insights into the pathophysiological mechanisms of many complicated diseases, although details of which remain unclear. Adiponectin, one of the most widely investigated adipokine, has been shown to possess both anti- and pro-inflammatory effects. RA is a chronic systemic inflammatory-related autoimmune disease. Accumulated evidence has demonstrated that cytokines and adipokines play an important role in the pathogenesis of RA. In this review, we have summarized the most recent advances in adiponectin research in the context of RA, focusing primarily on its effect on RA-related cells, its regulation on pro-inflammatory cytokines, as well as its validation as a biomarker for RA.     

Potential role of leptin, adiponectin and three novel adipokines--visfatin, chemerin and vaspin--in chronic hepatitis

Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Steatosis, independently of its metabolic or viral origin, leads to liver injury and fibrosis. It is suggested that hepatitis C virus may contribute to a wide spectrum of metabolic disturbances-namely, steatosis, insulin resistance, increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus and lipid metabolism abnormalities. Adipokines, which are produced mainly by adipose tissue, may influence the inflammatory response and insulin sensitivity and contribute to the development of metabolic abnormalities in CHC and also regulate fibrogenesis and angiogenesis. Visfatin was described as an adipokine with immunomodulating and proinflammatory properties that promotes B-cell maturation and enhances activation of leukocytes, synthesis of adhesion molecules and production of proinflammatory cytokines. Visfatin exerts insulin-mimetic effects, decreases plasma glucose levels and regulates cell energy balance. Chemerin stimulates chemotaxis of dendritic cells, macrophages and natural killer (NK) cells toward the site of inflammation. On the other hand, it inhibits synthesis of proinflammatory mediators and enhances adiponectin production, influences adipocyte differentiation and maturation and regulates glucose uptake in adipocytes. Vaspin expression in human adipose tissue seems to be a compensatory mechanism associated with obesity and insulin resistance. Vaspin suppresses leptin, tumor necrosis factor (TNF)-α and resistin expression. Leptin protects against liver steatosis but accelerates fibrosis progression and exacerbates the inflammatory process. In contrast, adiponectin exerts a hepatoprotective effect. In this report, data indicating a possible role of these adipokines in the pathogenesis of chronic hepatitis are summarized.     

The effect of PPARgamma ligands on the adipose tissue in insulin resistance

Insulin resistance is frequently accompanied by obesity and both obesity and type 2 diabetes are associated with a mild chronic inflammation. Elevated levels of various cytokines, such as TNF-alpha and IL-6, are typically found in the adipose tissue in these conditions. It has been suggested that many cytokines produced in the adipose tissue are derived from infiltrated inflammatory cells. However, the adipose tissue itself has proven to be an important endocrine organ, secreting several hormones and cytokines, usually referred to as adipokines. Peroxisome proliferator-activated receptor (PPAR)gamma is essential for adipocyte proliferation and differentiation. In recent years, PPARgamma and its ligands, the thiazolidinediones (TZD), have achieved great attention due to their insulin sensitizing and anti-inflammatory properties. Treatment with TZDs result in improved insulin signaling and adipocyte differentiation, increased adipose tissue influx of free fatty acids and inhibition of cytokine expression and action. As a result, PPARgamma plays a central role in maintaining a functional and differentiated adipose tissue.     

Relationship between obesity, inflammation and insulin resistance: new concepts

White adipose tissue is the main site of energy storage, but it is now recognized as an active participant in regulating physiologic and pathologic processes including immunity and inflammation. It has an endocrine function by secreting at least two main hormones, leptin and adiponectin. It can secrete other products, named adipokines, including cytokines and chemokines, involved in inflammation process. The release of adipokines by either adipocytes or adipose tissue infiltrated macrophages lead to a chronic sub-inflammatory state that could play a central role in cardiovascular complications linked to obesity and insulin resistance, a risk factor to develop type-2 diabetes.