Cytokine Production In Adipose Tissue Research Articles

Deferoxamine Interference in Fibro-inflammation: Additional Action in Control of Obese Adipose Tissue Dysfunction.

Several studies demonstrated that deferoxamine, an iron chelator, can improve inflammatory alterations in adipose tissue induced by obesity. Obesity alterations in adipose tissue are also associated with tissue remodeling, and deferoxamine has anti-fibrosis action previously described in sites like the skin and liver. In this work, we analyzed deferoxamine effects on adipose tissue fibro-inflammation during obesity induced by diet in mice. in vitro approaches with fibroblasts and macrophages were also carried out to elucidate deferoxamine activity. Our results demonstrated that in addition to exerting anti-inflammatory effects, reducing the cytokine production in adipose tissue of obese mice and by human monocyte differentiated in macrophage in vitro, deferoxamine can alter metalloproteinases expression and extracellular matrix production in vivo and in vitro. Deferoxamine could be an alternative to control fibro-inflammation in obese adipose tissue, contributing to the metabolic improvements previously described.

Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue

Obesity and the metabolic syndrome are characterized by chronic, low-grade inflammation mainly originating from expanding adipose tissue and resulting in inhibition of insulin signaling and disruption of glycemic control. Transgenic mice expressing human interleukin 37 (IL-37), an anti-inflammatory cytokine of the IL-1 family, are protected against metabolic syndrome when fed a high-fat diet (HFD) containing 45% fat. Here, we examined whether treatment with recombinant IL-37 ameliorates established insulin resistance and obesity-induced inflammation. WT mice were fed a HFD for 22 weeks and then treated daily with IL-37 (1 μg/mouse) during the last 2 weeks. Compared with vehicle only-treated mice, IL-37-treated mice exhibited reduced insulin in the plasma and had significant improvements in glucose tolerance and in insulin content of the islets. The IL-37 treatment also increased the levels of circulating IL-1 receptor antagonist. Cultured adipose tissues revealed that IL-37 treatment significantly decreases spontaneous secretions of IL-1β, tumor necrosis factor α (TNFα), and CXC motif chemokine ligand 1 (CXCL-1). We also fed mice a 60% fat diet with concomitant daily IL-37 for 2 weeks and observed decreased secretion of IL-1β, TNFα, and IL-6 and reduced intracellular levels of IL-1α in the liver and adipose tissue, along with improved plasma glucose clearance. Compared with vehicle treatment, these IL-37-treated mice had no apparent weight gain. In human adipose tissue cultures, the presence of 50 pm IL-37 reduced spontaneous release of TNFα and 50% of lipopolysaccharide-induced TNFα. These findings indicate that IL-37's anti-inflammatory effects can ameliorate established metabolic disturbances during obesity.

FNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in obesity

BackgroundObesity-induced chronic inflammation is critical in the pathogenesis of insulin resistance, and the recruitment and proinflammatory activation of adipose tissue macrophages (ATMs) is important for the development of this process. Here, we examined the effects of fibronectin type III domain-containing 5 (FNDC5) on inflammation and insulin resistance in high-fat diet-induced obese mice. Materials and MethodsMale wild-type (WT) and FNDC5−/− mice were fed with standard chow (Ctrl) or high fat diet (HFD) for 20 weeks to induce obesity and insulin resistance. Firstly, effects of FNDC5 gene deletion on obesity, insulin resistance, macrophage accumulation and polarization and adipose tissue inflammation were determined in mice. Secondly, the macrophage polarity shift was further examined with flow cytometry in isolated stromal vascular fraction (SVF). Thirdly, the effects of exogenous FNDC5 on lipopolysaccharide (LPS)-induced macrophage polarization, inflammation and the underlying signaling mechanism were investigated in RAW264.7 macrophages and primary mouse peritoneal cavity macrophages (PMs). Finally, the therapeutic effects of FNDC5 overexpression were examined in HFD-induced obese WT and FNDC5−/− mice. ResultsFNDC5 gene deletion aggravated obesity, insulin resistance, fat accumulation and inflammation accompanied with enhanced AMPK inhibition, macrophages recruitment and M1 polarization in mice fed with HFD. Exogenous FNDC5 inhibited LPS-induced M1 macrophage polarization and inflammatory cytokine production via AMPK phosphorylation in both RAW264.7 macrophages and PMs. FNDC5 overexpression attenuated insulin resistance, AMPK inhibition, M1 macrophage polarization and inflammatory cytokine production in adipose tissue of obese WT and FNDC5−/− mice. ConclusionsFNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in HFD-induced obesity. FNDC5 plays several beneficial roles in obesity and may be used as a therapeutic regimen for preventing inflammation and insulin resistance in obesity and diabetes.

Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression

Gluten exclusion (protein complex present in many cereals) has been proposed as an option for the prevention of diseases other than coeliac disease. However, the effects of gluten-free diets on obesity and its mechanisms of action have not been studied. Thus, our objective was to assess whether gluten exclusion can prevent adipose tissue expansion and its consequences. C57BL/6 mice were fed a high-fat diet containing 4.5% gluten (Control) or no gluten (GF). Body weight and adiposity gains, leukocyte rolling and adhesion, macrophage infiltration and cytokine production in adipose tissue were assessed. Blood lipid profiles, glycaemia, insulin resistance and adipokines were measured. Expression of the PPAR-α and γ, lipoprotein lipase (LPL), hormone sensitive lipase (HSL), carnitine palmitoyl acyltransferase-1 (CPT-1), insulin receptor, GLUT-4 and adipokines were assessed in epidydimal fat. Gluten-free animals showed a reduction in body weight gain and adiposity, without changes in food intake or lipid excretion. These results were associated with up-regulation of PPAR-α, LPL, HSL and CPT-1, which are related to lipolysis and fatty acid oxidation. There was an improvement in glucose homeostasis and pro-inflammatory profile-related overexpression of PPAR-γ. Moreover, intravital microscopy showed a lower number of adhered cells in the adipose tissue microvasculature. The overexpression of PPAR-γ is related to the increase of adiponectin and GLUT-4. Our data support the beneficial effects of gluten-free diets in reducing adiposity gain, inflammation and insulin resistance. The data suggests that diet gluten exclusion should be tested as a new dietary approach to prevent the development of obesity and metabolic disorders.

Thrombospondin1 Plays an Important Role in Obesity Associated Inflammation and Insulin Resistance

Copyright: © 2012 Wang S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Obesity is prevalent worldwide and is associated with the development of insulin resistance and type 2 diabetes. Obesity-induced chronic low-grade inflammation has been suggested to be an important mechanism for the development of IR [1]. Adipose tissue is a key organ for this chronic inflammatory response. Increased accumulation of adipose tissue macrophages (ATMs) has been demonstrated in obese rodents and humans by numerous studies [2,3]. It is now well established that ATMs are the primary source of inflammatory cytokine production in adipose tissue and play a key role in obesity-induced chronic low-grade inflammation and IR [2]. Although there have been some advances in the study of ATMs in obese conditions [2,4,5], the mechanisms underlying ATMs recruitment and activation remain to be determined.

Foenumoside B from Lysimachia foenum-graecum inhibits adipocyte differentiation and obesity induced by high-fat diet

We have previously reported anti-obesity effects of Lysimachia foenum-graecum in high-fat diet (HFD)-induced obesity model. Here we isolated a triterpene saponin foenumoside B as an active component of L. foenum-graecum. Foenumoside B blocked the differentiation of 3T3-L1 preadipocytes in a dose-dependent manner with an IC50 of 0.2μg/ml in adipogenesis assay and suppressed the induction of PPARγ, the master regulator of adipogenesis. Foenumoside B induced the activation of AMP-activated protein kinase (AMPK), and modulated the expression of genes involved in lipid metabolism towards lipid breakdown in differentiated adipocytes. In mouse model, oral administration of foenumoside B (10mg/kg/day for 6weeks) reduced HFD-induced body weight gain significantly without affecting food intake. Treatment of foenumoside B suppressed lipid accumulation in white adipose tissues and the liver, and lowered blood levels of glucose, triglycerides, ALT, and AST in HFD-induced obese mice. Consistent with the in vitro results, foenumoside B activated AMPK signaling, suppressed the expression of lipogenic genes, and enhanced the expression of lipolytic genes in vivo. Foenumoside B also blocked HFD-induced proinflammatory cytokine production in adipose tissue, suggesting its protective role against insulin resistance. Taken together, these findings demonstrate that foenumoside B represents the anti-obesity effects of L. foenum-graecum, and suggest therapeutic potential of foenumoside B in obesity and obesity-related metabolic diseases.

Dissociation of the Glucose and Lipid Regulatory Functions of FoxO1 by Targeted Knockin of Acetylation-Defective Alleles in Mice

FoxO1 integrates multiple metabolic pathways. Nutrient levels modulate FoxO1 acetylation, but the functional consequences of this posttranslational modification are unclear. To answer this question, we generated mice bearing alleles that encode constitutively acetylated and acetylation-defective FoxO1 proteins. Homozygosity for an allele mimicking constitutive acetylation (Foxo1(KQ/KQ)) results in embryonic lethality due to cardiac and angiogenesis defects. In contrast, mice homozygous fora constitutively deacetylated Foxo1 allele (Foxo1(KR/KR)) display a unique metabolic phenotype of impaired insulin action on hepatic glucose metabolism but decreased plasma lipid levels and low respiratory quotient that are consistent with a state of preferential lipid usage. Moreover, Foxo1(KR/KR) mice showa dissociation between weight gain and insulin resistance in predisposing conditions (high fat diet, diabetes, and insulin receptor mutations), possibly due to decreased cytokine production in adipose tissue. Thus, acetylation inactivates FoxO1 during nutrient excess whereas deacetylation selectively potentiates FoxO1 activity, protecting against excessive catabolism during nutrient deprivation.

The Expression and Regulation of Bone-acting Cytokines in Human Peripheral Adipose Tissue in Organ Culture

The humoral cross-talk between bone and fat is an area of increasing interest. We investigated the expression and regulation of the bone-acting cytokines; bone morphogenetic protein 2 (BMP2), connective tissue growth factor (CTGF), osteoprotegerin (OPG), and transforming growth factor beta (TGFB1). Subcutaneous adipose tissue was aspirated from lean, healthy women. Tissue samples were incubated with interleukin 1-β (IL1-β), tumor necrosis factor-α (TNF-α), cortisol, troglitazone, IL1-β + troglitazone, or vehicle. Gene expression in the adipose tissue was analyzed using qPCR and protein levels in the incubation media were analyzed using ELISA. OPG expression and secretion was diminished by 40.8% and 43.1% respectively, by cortisol, and OPG expression was diminished by 67.5% by troglitazone (p<0.05). The proinflammatory cytokines IL1-β and TNF-α significantly increased the expression of CTGF (p<0.05) by 65.1% and 101.3%, respectively, and the expression and secretion of OGP by 62.3-165.8% (p<0.05). This interleukin 1-β mediated increase in CTGF- and OPG expression and secretion was ameliorated by troglitazone. Troglitazone and related drugs are known to have adverse effects on bone. We suggest that this could be mediated via altered cytokine production in adipose tissue. Moreover, obese individuals have a low-grade inflammation in their adipose tissue and have higher bone mineral density than lean individuals. We suggest that this inflammation may increase the expression and secretion of OPG and CTGF and thereby increase BMD. In conclusion, bone acting cytokines are produced in the adipose tissue and may affect bone through endocrine mechanisms.

Lipid‐Heparin Infusion Suppresses the IL‐10 Response to Trauma in Subcutaneous Adipose Tissue in Humans

An imbalance between pro- and anti-inflammatory cytokine productions in adipose tissue is thought to contribute to chronic, systemic, low-grade inflammation and consequently to an increased risk of cardiovascular complications in obese and type 2 diabetic patients. Nonesterified fatty acids (NEFA), whose serum levels are elevated in such patients, have been shown to interfere with cytokine production in vitro. In order to evaluate the effects of elevated NEFA levels on cytokine production in adipose tissue in vivo we used an 18-gauge open-flow microperfusion (OFM) catheter to induce local inflammation in the subcutaneous adipose tissue (SAT) of healthy volunteers and to sample interstitial fluid (IF) specifically from the inflamed tissue. In two crossover studies, nine subjects received either an intravenous lipid-heparin infusion to elevate circulating NEFA levels or saline over a period of 28h. The former increased the circulating levels of triglycerides (TGs), NEFA, glucose, and insulin over the study period. NEFA effects on locally induced inflammation were estimated by measuring the levels of a panel adipokines in the OFM probe effluent. Interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) levels increased during the study period but were not affected by lipid-heparin infusion. In contrast, the level of IL-10, an anti-inflammatory cytokine, was significantly reduced during the final hour of lipid-heparin infusion (saline: 449.2 ± 105.9 vs. lipid-heparin: 65.4 ± 15.4pg/ml; P = 0.02). These data provide the first in vivo evidence that elevated NEFA can modulate cytokine production by adipose tissue.

Increased proinflammatory cytokine production in adipose tissue of obese patients with chronic kidney disease

Obesity is a known high-risk factor for the development of vascular diseases and chronic kidney disease (CKD). In this study we aimed to elucidate the impact of adipose tissue on the inflammatory state in CDK patients with obesity. A cohort of 40 patients with CKD (stages 3-4) with mild proteinuria (2.3-3.5 g/day) were analyzed in a prospective cross-sectional study: single blood samples and visceral and subcutaneous samples of adipose tissue were taken from 20 patients with obesity and 20 without obesity (control group) during elective abdominal surgery (laparoscopic cholecystectomy). Serum concentrations of asymmetric dimethylarginine (ADMA), adiponectin, C-reactive protein, interleukin-6, tumor necrosis factor-alpha, pentosidine and monocyte chemoattractant protein-1 were measured. Messenger RNA expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, adiponectin receptors 1 and 2, and immunocompetent cell marker CD68 was measured in subcutaneous and visceral fat samples using real-time PCR. Adipose tissue was examined immunohistochemically for CD68-positive cells. Other biochemical parameters (insulin, glycated hemoglobin, cholesterol, LDL cholesterol, and triglycerides) were assessed in the two groups of patients at the same time. Serum concentrations of ADMA, C-reactive protein, pentosidine, interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1 were significantly higher in obese CKD patients than in the control group; adiponectin was lower in the obese group. Subcutaneous and visceral mRNA expressions of tumor necrosis factor-alpha, CD68, adiponectin receptor-1, and monocyte chemoattractant protein-1 were significantly increased in the obese patients, whereas expression of adiponectin, interleukin-6, and adiponectin receptor-2 did not significantly differ between the patient groups. In general, mRNA expressions were higher in visceral than in subcutaneous samples (P < 0.01 vs. P < 0.05). Increased infiltration of subcutaneous and visceral adipose tissue by CD68-positive immunocompetent cells was found in the obese CKD group. With respect to lipid metabolism parameters, a small but significant increase in levels was found in the obese patients (P < 0.02). Changes in triglycerides were more marked in this group (P < 0.01) and a similar increase was noted in insulin and HbA1c levels (P < 0.02). Increased expression of proinflammatory cytokines and increased infiltration by immunocompetent cells were found in adipose tissue of obese patients with CKD stages 3-4. This upregulated inflammation may contribute to the induction of a systemic proinflammatory state in patients with CKD and could accelerate the progression of renal dysfunction.

Abstract 1124: CD40L Induces Inflammation in Adipose Tissue - a Potential Link Between the Metabolic Syndrome and Atherosclerosis

Background: CD40L figures prominently as marker and mediator of atherosclerosis and its clinical complications. Recent data also demonstrate an association between CD40L and the metabolic syndrome. In the light of these data we hypothesized a functional pro-inflammatory role of CD40L in adipose tissue that provokes systemic pro-inflammatory responses and potentially mediates some of the high cardiovascular risk associated with the metabolic syndrome. Methods and Results: Adipocytes and preadipocytes isolated from adipose tissue obtained from bariatic surgery did not express CD40L but its receptor CD40 as assessed by PCR and immunohistochemistry. Furthermore, sections of human adipose tissue from obese donors contained more macrophages and T cells colocalizing with CD40L than those from lean controls. Stimulation of both adipocytes and preadipocytes with recombinant CD40L resulted in a concentration- and time-dependent release of the pro-inflammatory cytokine IL-6, the chemokines MCP -1 and IL-8 as well as the inhibitor of fibrinolysis PAI-1 into the supernatant as quantified by ELISA. Membranes isolated from a Murine cell line overexpressing human CD40L reproduced these pro-inflammatory effects compared to respective controls. Interestingly, fenofibrate but neither rosiglitazone, metformin, nor atorvastatin attenuated the CD40L-inducible expression of these pro-atherogenic mediators. Finally, supernatants from adipocytes and preadipocytes stimulated with CD40L activated endothelial cells and macrophages, typical cell types resident in atherosclerotic lesions, as assessed by FACS for tissue factor, Mac-1, and ICAM-1, respectively. Conclusions: Our data suggest that CD40L induces inflammatory cytokine production in adipose tissue resulting in activation of endothelial cells and macrophages. This new mechanism may contribute to the high cardiovascular risk of patients suffering from the metabolic syndrome.

Dietary calcium and calcitriol regulation of the adipose tissue renin‐angiontensin system (RAS) and inflammatory cytokine production

Antagonism of the RAS may reduce type-2 diabetes risk, as angiotensin II modulates diabetogenic factors such as inflammatory cytokines and oxidative stress. Moreover, the local RAS modulates adipocyte function. Our previous data demonstrate that diet-induced obesity results in increased local oxidative stress and inflammatory cytokine production in adipose tissue, and that increasing dietary calcium attenuates this effect via regulation of calcitriol production. Accordingly, we investigated the effect of dietary calcium in regulation of the adipose tissue RAS in aP2-agouti transgenic mice and the role of RAS in modulating calcitriol regulation of inflammatory cytokine production in 3T3-L1 adipocytes. Dietary calcium significantly suppressed expression of angiotensinogen (80%, p<0.001), angiotensin II receptor type I (62%, p<0.001) and ACE (71%, p<0.001) in mouse visceral fat, suggesting that dietary calcium inhibits local RAS activity; RAS components were expressed at a lower level in subcutaneous adipose tissue, and each was comparably suppressed by dietary calcium (p=0.004). Moreover, calcitriol and angiotensin II each stimulated TNF α and IL-6 expression by ~2-fold in 3T3-L1 adipocytes (p<0.005), and the effect of calcitriol was attenuated by ACE inhibition with enalapril. Thus, the local RAS has a direct role in regulating inflammatory cytokine production in adipocytes, and calcitriol further promotes inflammatory cytokine production via a RAS-dependent mechanism. Collectively, these data suggest that dietary calcium regulates the local RAS in adipose tissue thereby inhibits inflammatory cytokine production.

Calcium‐dependent regulation of macrophage inhibitory factor and CD14 expression by calcitriol in human adipocytes

Obesity increases oxidative stress and inflammatory cytokine production in adipose tissue, and our recent data demonstrate that dietary calcium attenuates obesity-induced oxidative stress and inflammation. This effect may be explained by dietary calcium inhibition of calcitriol, which we have shown to stimulate reactive oxygen species and inflammatory cytokine production in cultured adipocytes. However, adipose tissue includes both endothelial cells and leukocytes as well as adipocytes; these appear to contribute to a low-grade inflammatory state in obesity. Accordingly, the interaction between adipocytes and leukocytes may play an important role in the local modulation of inflammation. Consequently, we investigated calcitriol modulation of the expression of macrophage inhibitory factor (MIF) and macrophage surface specific protein CD14, two key factors in regulating macrophage function and survival, in differentiated human adipocytes. Calcitriol markedly increased MIF and CD 14 expression by 59%(p=0.001) and 33%(p=0.008). respectively, while calcium channel antagonism with nifedipine completely reversed these effects, indicating that calcitriol stimulates MIF and CD14 expression via a calcium-dependent mechanism. Similar results were also observed in cultured 3T3-L1 adipocytes. These data suggest that calcitriol may regulate macrophage activity by modulating adipocyte production of factors associated with macrophage function. These data also provided additional explanation for our recent observations that suppression of calcitriol by dietary calcium decreases obesity associated oxidative stress and inflammation.