Resveratrol suppresses inflammatory responses and improves glucose uptake in adipocytes interacted with macrophages

Obesity is associated with inflammatory status and linked with metabolic syndrome. Interaction between adipocytes and macrophages aggravates inflammation and leads to insulin resistance in adipocytes. Resveratrol improved reportedly obesity-related inflammatory responses, but the effects of resveratrol on the production of inflammatory mediators and glucose metabolism in inflamed adipose tissue is not completely known. In this study, we investigated the effects of resveratrol on inflammatory change and insulin resistance in the coculture of hypertrophied 3T3-L1 adipocytes and RAW 264.7 macrophages. Resveratrol decreased nitric oxide production and the expression of interleukin (IL)-6, IL-1β, tumor necrosis factor-α, inducible nitric oxide synthesis, and cyclooxygenase-2 in the coculture. Resveratrol increased glucose uptake by stimulating the phosphorylation of IRS-1 and AKT in the coculture. These results support that resveratrol have beneficial effect on inflammation and insulin resistance in inflamed adipose tissue.     

Resveratrol potentiates glucose-stimulated insulin secretion in INS-1E beta-cells and human islets through a SIRT1-dependent mechanism

Resveratrol, a polyphenol compound, is known for its effects on energy homeostasis. With properties of energy sensors mediating effects of calorie restriction, sirtuins are targets of resveratrol. The mammalian sirtuin homolog SIRT1 is a protein deacetylase playing a role in glucose metabolism and islet function. Here, we investigated the effects of resveratrol and possible link with SIRT1 in β-cells. Insulinoma INS-1E cells and human islets were cultured with resveratrol before analyzing their physiological responses. Treatment of INS-1E cells for 24 h with 25 μM resveratrol resulted in marked potentiation of glucose-stimulated insulin secretion. This effect was associated with elevated glycolytic flux, resulting in increased glucose oxidation, ATP generation, and mitochondrial oxygen consumption. Such changes correlated with up-regulation of key genes for β-cell function, i.e. Glut2, glucokinase, Pdx-1, Hnf-1α, and Tfam. In human islets, chronic resveratrol treatment similarly increased both the glucose secretory response and expression of the same set of genes, eventually restoring the glucose response in islets obtained from one type 2 diabetic donor. Overexpression of Sirt1 in INS-1E cells potentiated resveratrol effects on insulin secretion. Conversely, inhibition of SIRT1 achieved either by expression of an inactive mutant or by using the EX-527 inhibitor, both abolished resveratrol effects on glucose responses. Treatment of INS-1E cells with EX-527 also prevented resveratrol-induced up-regulation of Glut2, glucokinase, Pdx-1, and Tfam. Resveratrol markedly enhanced the glucose response of INS-1E cells and human islets, even after removal of the compound from the medium. These effects were mediated by and fully dependent on active SIRT1, defining a new role for SIRT1 in the regulation of insulin secretion.     

Resveratrol directly affects in vitro lipolysis and glucose transport in human fat cells

Resveratrol is a naturally occurring polyphenol found in many dietary sources and red wine. Recognized as a cancer chemoprevention agent, an anti-inflammatory factor and an antioxidant molecule, resveratrol has been proposed as a potential anti-obesity compound and to be beneficial in diabetes. Most of the studies demonstrating the anti-adipogenic action of resveratrol were performed as long-term treatments on cultured preadipocytes. The aim of this study was to analyse the acute effects of resveratrol on glucose uptake and lipolysis in human mature adipocytes. Samples of subcutaneous abdominal adipose tissue were obtained from overweight humans and immediately digested by liberase. Fat cells were incubated (from 45 min to 4 h) with resveratrol 1 μM–1 mM. Then, glycerol release or hexose uptake was determined. Regarding lipolysis, the significant effects of resveratrol were found at 100 μM, consisting in a facilitation of isoprenaline stimulation and an impairment of insulin antilipolytic action. At 1 and 10 μM, resveratrol only tended to limit glucose uptake. Resveratrol 100 μM did not change basal glucose uptake but impaired its activation by insulin or by benzylamine. This inhibition was not found with other antioxidants. Such impairment of glucose uptake activation in fat cells may led to a reduced availability of glycerol phosphate and then to a decreased triacylglycerol assembly. Therefore, resveratrol increased triacylglycerol breakdown triggered by β-adrenergic activation and impaired lipogenesis. Consequently, our data indicate that resveratrol can be considered as limiting fat accumulation in human fat cells and further support its use for the mitigation of obesity.     

CTLA-4Ig immunotherapy of obesity-induced insulin resistance by manipulation of macrophage polarization in adipose tissues

It has been established that obesity alters the metabolic and endocrine function of adipose tissue and, together with accumulation of adipose tissue macrophages, contributes to insulin resistance. Although numerous studies have reported that shifting the polarization of macrophages from M1 to M2 can alleviate adipose tissue inflammation, manipulation of macrophage polarization has not been considered as a specific therapy. Here, we determined whether cytotoxic T-lymphocyte-associated antigen-4IgG1 (CTLA-4Ig) can ameliorate insulin resistance by induction of macrophages from proinflammatory M1 to anti-inflammatory M2 polarization in the adipose tissues of high fat diet-induced insulin-resistant mice. CTLA4-Ig treatment prevented insulin resistance by changing gene expression to M2 polarization, which increased the levels of arginase 1. Furthermore, flow cytometric analysis confirmed the alteration of polarization from CD11c (M1)- to CD206 (M2)-positive cells. Concomitantly, CTLA-4Ig treatment resulted in weight reductions of epididymal and subcutaneous adipose tissues, which may be closely related to overexpression of apoptosis inhibitors in macrophages. Moreover, proinflammatory cytokine and chemokine levels decreased significantly. In contrast, CCAAT enhancer binding protein α, peroxisome proliferator-activated receptor γ, and adiponectin expression increased significantly in subcutaneous adipose tissue. This novel mechanism of CTLA-4lg immunotherapy may lead to an ideal anti-obesity/inflammation/insulin resistance agent.     

Indomethacin Treatment Prevents High Fat Diet-induced Obesity and Insulin Resistance but Not Glucose Intolerance in C57BL/6J Mice

Chronic low grade inflammation is closely linked to obesity-associated insulin resistance. To examine how administration of the anti-inflammatory compound indomethacin, a general cyclooxygenase inhibitor, affected obesity development and insulin sensitivity, we fed obesity-prone male C57BL/6J mice a high fat/high sucrose (HF/HS) diet or a regular diet supplemented or not with indomethacin (±INDO) for 7 weeks. Development of obesity, insulin resistance, and glucose intolerance was monitored, and the effect of indomethacin on glucose-stimulated insulin secretion (GSIS) was measured in vivo and in vitro using MIN6 β-cells. We found that supplementation with indomethacin prevented HF/HS-induced obesity and diet-induced changes in systemic insulin sensitivity. Thus, HF/HS+INDO-fed mice remained insulin-sensitive. However, mice fed HF/HS+INDO exhibited pronounced glucose intolerance. Hepatic glucose output was significantly increased. Indomethacin had no effect on adipose tissue mass, glucose tolerance, or GSIS when included in a regular diet. Indomethacin administration to obese mice did not reduce adipose tissue mass, and the compensatory increase in GSIS observed in obese mice was not affected by treatment with indomethacin. We demonstrate that indomethacin did not inhibit GSIS per se, but activation of GPR40 in the presence of indomethacin inhibited glucose-dependent insulin secretion in MIN6 cells. We conclude that constitutive high hepatic glucose output combined with impaired GSIS in response to activation of GPR40-dependent signaling in the HF/HS+INDO-fed mice contributed to the impaired glucose clearance during a glucose challenge and that the resulting lower levels of plasma insulin prevented the obesogenic action of the HF/HS diet.     

Clodronate liposomes improve metabolic profile and reduce visceral adipose macrophage content in diet-induced obese mice

Background

Obesity-related adipose inflammation has been thought to be a causal factor for the development of insulin resistance and type 2 diabetes. Infiltrated macrophages in adipose tissue of obese animals and humans are an important source for inflammatory cytokines. Clodronate liposomes can ablate macrophages by inducing apoptosis. In this study, we aim to determine whether peritoneal injection of clodronate liposomes has any beneficial effect on systemic glucose homeostasis/insulin sensitivity and whether macrophage content in visceral adipose tissue will be reduced in diet-induced obese (DIO) mice.

Methodology/Principal Findings

Clodronate liposomes were used to deplete macrophages in lean and DIO mice. Macrophage content in visceral adipose tissue, metabolic parameters, glucose and insulin tolerance, adipose and liver histology, adipokine and cytokine production were examined. Hyperinsulinemic-euglycemic clamp study was also performed to assess systemic insulin sensitivity. Peritoneal injection of clodronate liposomes significantly reduced blood glucose and insulin levels in DIO mice. Systemic glucose tolerance and insulin sensitivity were mildly improved in both lean and DIO mice treated with clodronate liposomes by intraperitoneal (ip) injection. Hepatosteatosis was dramatically alleviated and suppression of hepatic glucose output was markedly increased in DIO mice treated with clodronate liposomes. Macrophage content in visceral adipose tissue of DIO mice was effectively decreased without affecting subcutaneous adipose tissue. Interestingly, levels of insulin sensitizing hormone adiponectin, including the high molecular weight form, were significantly elevated in circulation.

Conclusions/Significance

Intraperitoneal injection of clodronate liposomes reduces visceral adipose tissue macrophages, improves systemic glucose homeostasis and insulin sensitivity in DIO mice, which can be partially attributable to increased adiponectin levels.     

Adipolin/C1qdc2/CTRP12 protein functions as an adipokine that improves glucose metabolism

Obesity is a major risk factor for the development of insulin resistance and type 2 diabetes. Adipose tissue secretes various bioactive molecules, referred to as adipokines, whose dysregulation can mediate changes in glucose homeostasis and inflammatory responses. Here, we identify C1qdc2/CTRP12 as an insulin-sensitizing adipokine that is abundantly expressed by fat tissues and designate this adipokine as adipolin (adipose-derived insulin-sensitizing factor). Adipolin expression in adipose tissue and plasma was reduced in rodent models of obesity. Adipolin expression was also decreased in cultured 3T3-L1 adipocytes by treatment with inducers of endoplasmic reticulum stress and inflammation. Systemic administration of adipolin ameliorated glucose intolerance and insulin resistance in diet-induced obese mice. Adipolin administration also reduced macrophage accumulation and proinflammatory gene expression in the adipose tissue of obese mice. Conditioned medium from adipolin-expressing cells diminished the expression of proinflammatory cytokines in response to stimulation with LPS or TNFα in cultured macrophages. These data suggest that adipolin functions as an anti-inflammatory adipokine that exerts beneficial actions on glucose metabolism. Therefore, adipolin represents a new target molecule for the treatment of insulin resistance and diabetes.     

The Full Capacity of AICAR to Reduce Obesity-Induced Inflammation and Insulin Resistance Requires Myeloid SIRT1

Chronic Inflammation is a key link between obesity and insulin resistance. We previously showed that two nutrient sensors AMP-activated protein kinase (AMPK) and SIRT1 interact to regulate macrophage inflammation. AMPK is also a molecular target of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), which has been shown to reduce insulin resistance in various animal models. Here we aim to determine whether the therapeutic effects of AICAR against insulin resistance involve its anti-inflammatory function, which requires macrophage SIRT1. Long-term administration of low-dose AICAR significantly suppressed adipose inflammation in established diet-induced obese mice. This was associated with improved glucose homeostasis and insulin sensitivity without changes of body weight. In contrast, SIRT1 deletion in myeloid SIRT1 knockout (MSKO) mice increased infiltration of classically activated M1 macrophages and decreased alternatively activated M2 macrophages in adipose tissue. As a result, MSKO mice on high fat (HF) diets exhibited impaired insulin signaling in skeletal muscle, fat, and liver, and developed systemic insulin resistance in glucose tolerance tests, insulin tolerance tests, and hyperinsulinemic-euglycemic clamp experiments. Interestingly, the beneficial effects of AICAR on adipose inflammation and insulin sensitivity were absent in MSKO mice fed HF diets, suggesting that the full capacity of AICAR to antagonize obesity-induced inflammation and insulin resistance requires myeloid SIRT1. In summary, AICAR negatively regulates HF diet-induced inflammation, which requires myeloid SIRT1, thereby contributing to the protection against insulin resistance. Myeloid SIRT1 is a therapeutic target of the anti-inflammatory and insulin-sensitizing effects of AICAR.     

The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance

Over the past decade, chronic inflammation in visceral adipose tissue (VAT) has gained acceptance as a lead promoter of insulin resistance in obesity. A great deal of evidence has pointed to the role of adipokines and innate immune cells, in particular, adipose tissue macrophages, in the regulation of fat inflammation and glucose homeostasis. However, more recently, cells of the adaptive immune system, specifically B and T lymphocytes, have emerged as unexpected promoters and controllers of insulin resistance. These adaptive immune cells infiltrate obesity expanded VAT and through cytokine secretion and macrophage modulation dictate the extent of the local inflammatory response, thereby directly impacting insulin resistance. The remarkable ability of our adaptive immune system to regulate insulin sensitivity and metabolism has unmasked a novel physiological function of this system, and promises new diagnostic and therapeutic strategies to manage the disease. This review highlights critical roles of adipose tissue lymphocytes in governing glucose homeostasis.     

Loss of ovarian function in association with a high-fat diet promotes insulin resistance and disturbs adipose tissue immune homeostasis

Loss of ovarian function, as occurs in menopause or after ovariectomy (OVX), is associated with insulin resistance. Adipose tissue inflammation is suggested to be a key component of obesity-induced insulin resistance in male rodents. However, little is known about the effect of OVX and diet on insulin resistance in association with immune homeostasis. Thus, we conducted this study to determine how high-fat diet (HFD) and OVX, alone or in combination, impacted adipose tissue inflammation and insulin resistance. Nine-week-old sham and OVX-treated C57Bl/6 mice were fed low-fat diet (LFD) or HFD (60%) up to 16 weeks. Glucose metabolism was assessed, and adipose tissue and spleen were characterized for tissue inflammation and immune cell populations. First, we found that HFD induced glucose intolerance in both OVX mice and, to a lesser extent, sham mice. OVX mice fed LFD showed no difference in glucose intolerance compared to sham mice. Additionally, OVX mice only when exposed to HFD displayed a proinflammatory profile in adipose tissue: increased macrophages together with dominant M1-like phenotype and also increased T cells, B cells and NK cells compared to those with intact ovarian function. Together, our findings indicate that loss of ovarian function coupled with an HFD intake promotes insulin resistance and adipose tissue inflammation by disturbing adipose tissue immune homeostasis. These findings have a clinical implication in the dietary guidance for menopausal women.     

Effects of spironolactone on glucose transport and interleukin-6 secretion in adipose cells of women.

Adipose tissue inflammation and insulin resistance are central to the pathogenesis of the metabolic syndrome. Spironolactone, an antagonist of mineralocorticoid receptor, glucocorticoid receptor and androgen receptor, and agonist of progesterone receptor, has anti-inflammatory activity. Blockade of the renin-angiotensin-aldosterone system has been shown to improve glucose metabolism. We have investigated whether spironolactone has direct effects on glucose uptake and interleukin-6 secretion in human adipocytes. Spironolactone, but not its active metabolite canrenoic acid, significantly increased basal and insulin-stimulated glucose uptake in cultured IN VITRO-differentiated adipocytes of women, without affecting insulin sensitivity. The effect was not due to changes in abundance of glucose transporters 1 or 4 or in degree of cell differentiation. Spironolactone, but not canrenoic acid, significantly reduced basal interleukin-6 secretion by cultured stromal-vascular cells. These effects of spironolactone were not mediated by ligand-dependent antagonism of the mineralocorticoid, glucocorticoid, or androgen receptors. Spironolactone may have a novel role in increasing glucose uptake into adipose cells and attenuating adipose tissue inflammation, with implications for management of metabolic syndrome.     

Decreased AMP-activated protein kinase activity is associated with increased inflammation in visceral adipose tissue and with whole-body insulin resistance in morbidly obese humans

Inflammation and infiltration of immune cells in white adipose tissue have been implicated in the development of obesity-associated insulin resistance. Likewise, dysregulation of the fuel-sensing enzyme AMP-activated protein kinase (AMPK) has been proposed as a pathogenetic factor for these abnormalities based on both its links to insulin action and its anti-inflammatory effects. In this study, we examined the relationships between AMPK activity, the expression of multiple inflammatory markers in visceral (mesenteric and omental) and abdominal subcutaneous adipose tissue, and whole-body insulin sensitivity in morbidly obese patients (BMI 48 ± 1.9 kg/m²) undergoing gastric bypass surgery. AMPK activity was assessed by Western-blots (P-AMPK/T-AMPK) and mRNA levels of various markers of inflammation by qRT-PCR. Patients were stratified as insulin sensitive obese or insulin-resistant obese according to their HOMA-IR values. The results indicate that AMPK activity is lower in visceral than in subcutaneous abdominal adipose tissue of these patients and that this is associated with an increased expression of multiple inflammatory genes. They also revealed that AMPK activity is lower in adipose tissue of obese patients who are insulin resistant (HOMA-IR > 2.3) than in BMI-matched insulin sensitive subjects. Furthermore, this difference was evident in all three fat depots. In conclusion, the data suggest that there are close links between reduced AMPK activity and inflammation in white adipose tissue, and whole-body insulin resistance in obese humans. Whether adipose tissue AMPK dysregulation is a causal factor for the development of the inflammation and insulin resistance remains to be determined.     

Deletion of Hypoxia-Inducible Factor-1α in Adipocytes Enhances Glucagon-Like Peptide-1 Secretion and Reduces Adipose Tissue Inflammation

It is known that obese adipose tissues are hypoxic and express hypoxia-inducible factor (HIF)-1α. Although some studies have shown that the expression of HIF-1α in adipocytes induces glucose intolerance, the mechanisms are still not clear. In this study, we examined its effects on the development of type 2 diabetes by using adipocyte-specific HIF-1α knockout (ahKO) mice. ahKO mice showed improved glucose tolerance compared with wild type (WT) mice. Macrophage infiltration and mRNA levels of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor α (TNFα) were decreased in the epididymal adipose tissues of high fat diet induced obese ahKO mice. The results indicated that the obesity-induced adipose tissue inflammation was suppressed in ahKO mice. In addition, in the ahKO mice, serum insulin levels were increased under the free-feeding but not the fasting condition, indicating that postprandial insulin secretion was enhanced. Serum glucagon-like peptide-1 (GLP-1) levels were also increased in the ahKO mice. Interestingly, adiponectin, whose serum levels were increased in the obese ahKO mice compared with the obese WT mice, stimulated GLP-1 secretion from cultured intestinal L cells. Therefore, insulin secretion may have been enhanced through the adiponectin-GLP-1 pathway in the ahKO mice. Our results suggest that the deletion of HIF-1α in adipocytes improves glucose tolerance by enhancing insulin secretion through the GLP-1 pathway and by reducing macrophage infiltration and inflammation in adipose tissue.     

Chronic ethanol and triglyceride turnover in white adipose tissue in rats: inhibition of the anti-lipolytic action of insulin after chronic ethanol contributes to increased triglyceride degradation

Chronic ethanol consumption disrupts whole-body lipid metabolism. Here we tested the hypothesis that regulation of triglyceride homeostasis in adipose tissue is vulnerable to long-term ethanol exposure. After chronic ethanol feeding, total body fat content as well as the quantity of epididymal adipose tissue of male Wistar rats was decreased compared with pair-fed controls. Integrated rates of in vivo triglyceride turnover in epididymal adipose tissue were measured using (2)H(2)O as a tracer. Triglyceride turnover in adipose tissue was increased due to a 2.3-fold increase in triglyceride degradation in ethanol-fed rats compared with pair-fed controls with no effect of ethanol on triglyceride synthesis. Because increased lipolysis accompanied by the release of free fatty acids into the circulation is associated with insulin resistance and liver injury, we focused on determining the mechanisms for increased lipolysis in adipose tissue after chronic ethanol feeding. Chronic ethanol feeding suppressed beta-adrenergic receptor-stimulated lipolysis in both in vivo and ex vivo assays; thus, enhanced triglyceride degradation during ethanol feeding was not due to increased beta-adrenergic-mediated lipolysis. Instead, chronic ethanol feeding markedly impaired insulin-mediated suppression of lipolysis in conscious rats during a hyperinsulinemic-euglycemic clamp as well as in adipocytes isolated from epididymal and subcutaneous adipose tissue. These data demonstrate for the first time that chronic ethanol feeding increased the rate of triglyceride degradation in adipose tissue. Furthermore, this enhanced rate of lipolysis was due to a suppression of the anti-lipolytic effects of insulin in adipocytes after chronic ethanol feeding.     

Palmitate- and lipopolysaccharide-activated macrophages evoke contrasting insulin responses in muscle cells

Factors secreted by macrophages contribute to whole body insulin resistance, acting in part on adipose tissue. Muscle is the major tissue for glucose disposal, but how macrophage-derived factors impact skeletal muscle glucose uptake is unknown, or whether the macrophage environment influences this response. We hypothesized that conditioned medium from macrophages pretreated with palmitate or LPS would directly affect insulin action and glucose uptake in muscle cells. L6-GLUT4myc myoblasts were exposed to conditioned medium from RAW 264.7 macrophages pretreated with palmitate or LPS. Conditioned medium from palmitate-treated RAW 264.7 macrophages inhibited myoblast insulin-stimulated glucose uptake, GLUT4 translocation, and Akt phosphorylation while activating JNK p38 MAPK, decreasing IkappaBalpha, and elevating inflammation markers. Surprisingly, and opposite to its effects on adipose cells, conditioned medium from LPS-treated macrophages stimulated myoblast insulin-stimulated glucose uptake, GLUT4 translocation, and Akt phosphorylation without affecting stress kinases or inflammation indexes. This medium had markedly elevated IL-10 levels, and IL-10, alone, potentiated insulin action in myoblasts and partly reversed the insulin resistance imparted by medium from palmitate-treated macrophages. IL-10 neutralizing antibodies blunted the positive influence of LPS macrophage-conditioned medium. We conclude that myoblasts and adipocytes respond differently to cytokines. Furthermore, depending on their environment, macrophages negatively or positively influence muscle cells. Macrophages exposed to palmitate produce a mixture of proinflammatory cytokines that reduce insulin action in muscle cells; conversely, LPS-activated macrophages increase insulin action, likely via IL-10. Macrophages may be an integral element in glucose homeostasis in vivo, relaying effects of circulating factors to skeletal muscle.     

白藜芦醇对成年期追赶生长大鼠体成分的影响及机制

目的:观察白藜芦醇对成年期追赶生长大鼠体成分的影响及可能机制。方法:8周龄雄性 SD 大鼠分为6组(共2个时间点),即4周时间点3组:正常饮食4周 (NC4)组、热卡限制4周(R4)组,热卡限制同时白藜芦醇治疗(R4E)组;12周时间点3组:正常饮食12周(NC12)组,追赶生长(CUG)组,追赶生长白藜芦醇治疗(CUGE)组。每组含6只大鼠,白藜芦醇用生理盐水配制成一定浓度悬浊液,按100 mg/(kg·d)剂量予实验动物灌胃治疗。实验第4周、12周检测体重、躯干和全身的肌肉及脂肪含量、躯干与全身脂肪比例,实验第12周检测骨骼肌与附睾脂肪组织SIRT1的表达,附睾脂肪组织PPARγ的表达。结果:与NC12组相比,CUG组躯干及全身的脂肪含量、躯干与全身脂肪比例、附睾脂肪组织PPARγ的表达均明显升高(P＜0.05),肌肉含量、骨骼肌与附睾脂肪组织SIRT1的表达显著降低(P＜0.05或P＜0.01);与CUG组相比,经白藜芦醇干预后的CUGE组全身的脂肪含量、躯干与全身脂肪比例、附睾脂肪组织PPARγ的表达均明显降低(P＜0.05),肌肉含量、骨骼肌与附睾脂肪组织SIRT1的表达较CUG组显著提高(P＜0.05)。结论:白藜芦醇降低成年期追赶生长大鼠体脂含量,增加肌肉含量,改善腹部脂肪堆积,其机制可能与增加骨骼肌及内脏脂肪组织SIRT1表达,抑制内脏脂肪PPARγ的表达有关。     

Resveratrol protects against polychlorinated biphenyl-mediated impairment of glucose homeostasis in adipocytes

Resveratrol (RSV) is a plant polyphenol that exhibits several favorable effects on glucose homeostasis in adipocytes. Recent studies from our laboratory demonstrated that coplanar polychlorinated biphenyls (PCBs) that are ligands of the aryl hydrocarbon receptor impair glucose homeostasis in mice. PCB-induced impairment of glucose homeostasis was associated with augmented expression of inflammatory cytokines in adipose tissue, a site for accumulation of lipophilic PCBs. This study determined if RSV protects against PCB-77 induced impairment of glucose disposal in vitro and in vivo and if these beneficial effects are associated with enhanced nuclear factor erythoid 2-related factor 2 (Nrf2) signaling in adipose tissue. PCB-77 increased oxidative stress and abolished insulin stimulated 2-deoxy-d-glucose uptake in 3 T3-L1 adipocytes. These effects were restored by RSV, which resulted in a concentration-dependent increase in NAD(P)H:quinone oxidoreductase 1 (NQO1), the downstream target of Nrf2 signaling. We quantified glucose and insulin tolerance and components of Nrf2 and insulin signaling cascades in adipose tissue of male C57BL/6 mice administered vehicle or PCB-77 (50 mg/kg) and fed a diet with or without resVida (0.1%, or 160 mg/kg per day). PCB-77 impaired glucose and insulin tolerance, and these effects were reversed by RSV. PCB-77 induced reductions in insulin signaling in adipose tissue were also abolished by RSV, which increased NQO1 expression. These results demonstrate that coplanar PCB-induced impairment of glucose homeostasis in mice can be prevented by RSV, potentially through stimulation of Nrf2 signaling and enhanced insulin stimulated glucose disposal in adipose tissue.     

Macrophage Migration Inhibitory Factor Deficiency Ameliorates High-Fat Diet Induced Insulin Resistance in Mice with Reduced Adipose Inflammation and Hepatic Steatosis

Macrophage infiltration is a critical determinant of high-fat diet induced adipose tissue inflammation and insulin resistance. The precise mechanisms underpinning the initiation of macrophage recruitment and activation are unclear. Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, displays chemokine-like properties. Circulating MIF levels are elevated during obesity however its role in high-fat diet induced adipose inflammation and insulin resistance remains elusive. Wildtype and MIF^−/− C57Bl\6J mice were fed chow or high-fat diet. Body weight and food intake was assessed. Glucose homeostasis was monitored by glucose and insulin tolerance tests. Adipose tissue macrophage recruitment and adipose tissue insulin sensitivity was evaluated. Cytokine secretion from stromal vascular fraction, adipose explants and bone marrow macrophages was measured. Inflammatory signature and insulin sensitivity of 3T3-L1-adipocytes co-cultured with wildtype and MIF^−/− macrophage was quantified. Hepatic triacylglyceride levels were assessed. MIF^−/− exhibited reduced weight gain. Age and weight-matched obese MIF^−/− mice exhibited improved glucose homeostasis coincident with reduced adipose tissue M1 macrophage infiltration. Obese MIF^−/− stromal vascular fraction secreted less TNFα and greater IL-10 compared to wildtype. Activation of JNK was impaired in obese MIF^−/−adipose, concomitant with pAKT expression. 3T3-L1-adipocytes cultured with MIF^−/− macrophages had reduced pro-inflammatory cytokine secretion and improved insulin sensitivity, effects which were also attained with MIF inhibitor ISO-1. MIF^−/− liver exhibited reduced hepatic triacyglyceride accumulation, enhanced pAKT expression and reduced NFκB activation. MIF deficiency partially protects from high-fat diet induced insulin resistance by attenuating macrophage infiltration, ameliorating adipose inflammation, which improved adipocyte insulin resistance ex vivo. MIF represents a potential therapeutic target for treatment of high-fat diet induced insulin resistance.