Low-grade Inflammation In Obesity Research Articles

Chronic spontaneous urticaria and metabolic syndrome: a relationship conundrum.

Chronic spontaneous urticaria (CSU) and metabolic syndrome (MetS) are associated with low-grade inflammation. Despite intensive research and various hypothesis, there is lack of specific pathomechanisms of urticaria. Previous studies have suggested low-grade inflammation in obesity which may be linked to urticaria. However, there is limited literature on association of MetS and CSU. So, this study was conducted to evaluate the association of MetS and its components in patients with CSU. This was a hospital-based and cross-sectional cohort study in which 481 patients of CSU and 240 age- and gender-matched controls were recruited. MetS was defined using the revised National Cholesterol Education Program Adult Treatment Panel III. BMI, waist circumference, blood pressure, fasting blood sugar, plasma insulin, and lipid profile were measured after overnight fasting. Pearson's Chi-squared test was used to calculate significance. Logistic regression analysis was done to assess MetS as a predictor of CSU. All patients were started on antihistamines according to the severity of the disease. CSU patients comprised 220 men (45.7%) and 261 women (54.3%) with 97 patients (20.12%) qualifying criteria for metabolic syndrome compared with 73 (30.42%) controls without any significant difference (p = 0.177). CSU was significantly associated with a higher prevalence of central obesity (p = 0.003) but CSU patients with central obesity did not have a higher urticaria activity score (p = 0.727) or serum IgE levels (p = 0.359). In conclusion, our study found an increased association of central obesity with CSU that was not related to the severity of urticaria. This is of significance as obesity is the most prevalent and first component of MetS to be developed. There was no increase in the overall prevalence of MetS in patients with CSU. The increased association of obesity and urticaria in our study can be partially explained by the role of antihistamines in modulation of metabolic pathway and appetite. Future research into the same can give better insights and thus can aid in better management options in CSU patients.

Phenolic Compounds Known to Be Present in Lingonberry (Vaccinium vitis-idaea L.) Enhance Macrophage Polarization towards the Anti-Inflammatory M2 Phenotype.

Macrophages are pleiotropic immune cells whose phenotype can polarize towards the pro-inflammatory M1 or anti-inflammatory M2 direction as a response to environmental changes. In obesity, the number of macrophages in adipose tissue is enhanced, and they shift towards the M1 phenotype. Activated M1 macrophages secrete pro-inflammatory cytokines and adipokines involved in the development of systemic low-grade inflammation, complicating obesity. Polyphenols are widely found in the vegetable kingdom and have anti-inflammatory properties. We and others have recently found that lingonberry (Vaccinium vitis-idaea L.) supplementation is able to prevent the development of low-grade inflammation and its metabolic consequences in experimentally induced obesity. In the present study, we investigated the effects of twelve phenolic compounds known to be present in lingonberry (resveratrol, piceid, quercetin, kaempferol, proanthocyanidins, delphinidin, cyanidin, benzoic acid, cinnamic acid, coumaric acid, caffeic acid, and ferulic acid) on macrophage polarization, which is a meaningful mechanism determining the low-grade inflammation in obesity. Mouse J774 and human U937 macrophages and commercially available phenolic compounds were used in the studies. Three of the twelve compounds investigated showed an effect on macrophage polarization. Resveratrol, kaempferol, and proanthocyanidins enhanced anti-inflammatory M2-type activation, evidenced as increased expression of Arg-1 and MRC-1 in murine macrophages and CCL-17 and MRC-1 in human macrophages. Resveratrol and kaempferol also inhibited pro-inflammatory M1-type activation, shown as decreased expression of IL-6, NO, and MCP-1 in murine macrophages and TNF-α and IL-6 in human macrophages. In the further mechanistic studies, the effects of the three active compounds were investigated on two transcription factors important in M2 activation, namely on PPARγ and STAT6. Resveratrol and kaempferol were found to enhance PPARγ expression, while proanthocyanidins increased the phosphorylation of STAT6. The results suggest proanthocyanidins, resveratrol, and kaempferol as active constituents that may be responsible for the positive anti-inflammatory effects of lingonberry supplementation in obesity models. These data also extend the previous knowledge on the anti-inflammatory effects of lingonberry and encourage further studies to support the use of lingonberry and lingonberry-based products as a part of a healthy diet.

Leptin Signaling Suppression in Macrophages Improves Immunometabolic Outcomes in Obesity.

Obesity is a major concern for global health care systems. Systemic low-grade inflammation in obesity is a major risk factor for insulin resistance. Leptin is an adipokine secreted by the adipose tissue that functions by controlling food intake, leading to satiety. Leptin levels are increased in obesity. Here, we show that leptin enhances the effects of LPS in macrophages, intensifying the production of cytokines, glycolytic rates, and morphological and functional changes in the mitochondria through an mTORC2-dependent, mTORC1-independent mechanism. Leptin also boosts the effects of IL-4 in macrophages, leading to increased oxygen consumption, expression of macrophage markers associated with a tissue repair phenotype, and wound healing. In vivo, hyperleptinemia caused by diet-induced obesity increases the inflammatory response by macrophages. Deletion of leptin receptor and subsequently of leptin signaling in myeloid cells (ObR-/-) is sufficient to improve insulin resistance in obese mice and decrease systemic inflammation. Our results indicate that leptin acts as a systemic nutritional checkpoint to regulate macrophage fitness and contributes to obesity-induced inflammation and insulin resistance. Thus, specific interventions aimed at downstream modulators of leptin signaling may represent new therapeutic targets to treat obesity-induced systemic inflammation.

Remodeling of Macrophages in White Adipose Tissue under the Conditions of Obesity as well as Lipolysis.

Adipose tissue macrophages (ATM) are a major source of low-grade inflammation in obesity, and yet reasons driving ATM accumulation in white adipose tissue (WAT) are not fully understood. Emerging evidence suggested that ATM underwent extensive remodeling in obesity. In addition to abundance, ATM in obesity were lipid-laden and metabolically reprogrammed, which in turn was tightly related to their functional alterations and persistence in obesity. Herein, we aimed to discuss that activation of lipid sensing signaling associated with metabolic reprogramming in ATM was indispensible for their migration, retention, or proliferation in obesity. Likewise, lipolysis also induced similar but transient ATM remodeling. Therefore, we assumed that obesity might share overlapping mechanisms with lipolysis in remodeling ATM. Formation of crown-like structures (CLS) in WAT was presumably a common event initiating ATM remodeling, with a spectrum of lipid metabolites released from adipocytes being potential signaling molecules. Moreover, adipose interlerkin-6 (IL-6) exhibited homologous alterations by obesity and lipolysis. Thus, we postulated a positive feedback loop between ATM and adipocytes via IL-6 signaling backing ATM persistence by comparison of ATM remodeling under obesity and lipolysis. An elucidation of ATM persistence could help to provide novel therapeutic targets for obesity-associated inflammation.

Dietary ω-3 polyunsaturated fatty acids modulate CD4+ T-cell subset markers, adipocyte antigen-presentation potential, and NLRP3 inflammasome activity in a coculture model of obese adipose tissue

ObjectivesChronic low-grade inflammation in obesity is partly driven by inflammatory cross talk between adipocytes and interferon-γ-secreting CD4+ T-helper (Th)1 cells, a process we have shown may be mitigated by long-chain (LC) ω-3 polyunsaturated fatty acids (PUFAs). Our objective was to study pivotal mediators of interactions between Th1 cells and adipocytes as potential mechanisms underlying the antiinflammatory effects of LC ω-3 PUFAs. MethodsUsing an in vitro model, 3T3-L1 adipocytes were cocultured with purified splenic CD4+ T cells from C57BL/6 mice consuming one of two isocaloric high-fat (HF) diets (60% kcal fat), containing either 41.2% kcal from lard + 18.7% kcal from corn oil (control, HF) or 41.2% kcal from lard + 13.4% kcal from corn oil + 5.3% kcal from fish oil (HF+FO). Cocultures were stimulated for 48 h with lipopolysaccharide (10 ng/mL). ResultsCompared with HF cocultures, HF+FO reduced Th1-cell markers (including secreted interferon-γ) and increased Th2-cell markers, consistent with reduced expression of genes related to major histocompatibility complex II (P < 0.05). HF+FO also blunted markers of priming and activity of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome (P < 0.05). In confirmatory work, 3T3-L1 adipocyte pretreatment with the LC ω-3 PUFA docosahexaenoic acid (100 μM, 24 h) blunted interferon-γ-induced (5 ng/mL, 24 h) expression of genes related to major histocompatibility complex II and priming and activity markers of the NLRP3 inflammasome compared with control (P < 0.05). ConclusionsInflammatory interactions between CD4+ T cells and adipocytes may provide a target for LC ω-3 PUFAs to mitigate obesity-associated inflammation.

Lung Regulatory T Cells Express Adiponectin Receptor 1: Modulation by Obesity and Airway Allergic Inflammation.

Regulatory T cells (Tregs) decrease in the adipose tissue upon weight gain, contributing to persistent low-grade inflammation in obesity. We previously showed that adipose tissue Tregs express the adiponectin receptor 1 (AdipoR1); however, the expression in lung Tregs is still unknown. Here, we aimed to determine whether Helios+ and Helios− Treg subsets expressed AdipoR1 in the lungs of obese mice and whether different obesity grades affected the expression upon allergic lung inflammation. For diet-induced obesity (DIO), mice were fed a high-fat diet (HFD) for up to 15 weeks (overweight), 21 weeks (obesity), and 26 weeks (morbid obesity). Overweight and morbidly obese mice were sensitized and challenged with ovalbumin (OVA) to induce allergic lung inflammation. The AdipoR1 expression was reduced significantly in the lung Helios+ and Helios− Tregs of obese mice compared with lean mice. Airway allergic inflammation showed reduced AdipoR1 expression in lung Foxp3+ Tregs. Obesity significantly exacerbated the eosinophilic airway inflammation and reduced the number of Helios+ Tregs in lung and adipose tissue in the obesity-associated asthma model. Upon further weight gain, AdipoR1-expressing Tregs in the lungs of allergic mice were increased, whereas AdipoR1-expressing Tregs in adipose tissue were reduced. These data suggest that obesity-associated adipose tissue inflammation may exacerbate allergic inflammation by downregulating the AdipoR1+ Tregs in the lungs.

Plasma levels of soluble urokinase plasminogen activator receptor (suPAR) and high-sensitivity C-reactive protein after Roux-en-Y gastric bypass or sleeve gastrectomy: a 1-year prospective observational study.

Low-grade inflammation in obesity contributes to the development of cardiovascular disease, diabetes mellitus and cancer, and is associated with increased mortality. The purpose of this 1-year prospective observational study was to examine the weight loss effect of bariatric surgery on plasma concentrations of two inflammatory markers, namely high-sensitivity C-reactive protein (hsCRP) and soluble urokinase-type plasminogen activator receptor (suPAR), in patients with obesity. Sixteen subjects without obesity and 32 patients with obesity class III, who had already settled upon Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) were included in the study. Subjects without obesity were examined once, at baseline; patients with obesity were examined preoperatively (baseline) and 3, 6 and 12months postoperatively. Plasma suPAR and hsCRP concentrations at baseline were higher in patients with obesity than in lean participants (2.68 ± 0.86 vs 1.86 ± 0.34ng/mL, p < 0.001 and 9.83 ± 9.55 vs 1.36 ± 1.95mg/dL, p < 0.001). Levels of suPAR following bariatric surgery increased significantly 3months after either RYGB or SG (3.58 ± 1.58 vs 3.26 ± 0.7ng/mL, respectively) and declined at 6 (3.19 ± 1.75 vs 2.8 ± 0.84ng/mL, respectively) and 12months (2.6 ± 1.5 vs 2.22 ± 0.49ng/mL, respectively; p < 0.05 for the effect of time on suPAR levels during the study), whereas those of hsCRP declined consistently after bariatric surgery (3months: 5.44 ± 3.99 vs 9.47 ± 11.98mg/dL, respectively; 6months; 5.39 ± 5.6 vs 10.25 ± 17.22mg/dL, respectively; and 12months: 2.23 ± 2.5 vs 3.07 ± 3.63mg/dL, respectively; p < 0.001 for the effect of time on hsCRP levels during the study). 1-year change in BMI was negatively associated with suPAR levels at 12months. Our findings support an association between obesity and low-grade inflammation. Weight loss following bariatric surgery is associated with a consistent decline in plasma hsCRP, while plasma suPAR levels increase at 3months and decline by 12months.

Supplementation of pyrroloquinoline quinone with atorvastatin augments mitochondrial biogenesis and attenuates low grade inflammation in obese rats

Mitochondrial dysfunction and Inflammation play a significant role in the manifestation of the co-morbidities of obesity. The study deciphered the impact of Pyrroloquinoline quinone (PQQ) per se and with Atorvastatin (ATS) on high fat, 10% fructose diet (HFFD) induced obese rats expressing low-grade inflammation, dyslipidemia, and mitochondrial dysfunction. HFFD was fed for 10 weeks followed by treatment for 5 weeks with ATS 10 or 20 mg/kg, PQQ 10 or 20 mg/kg, p.o. per se or their combinations. The impact on blood glucose, lipid profile and serum insulin, TNF-α, IL-1β, IL-18, IL-6 was estimated. Gene and protein expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC 1α), Sirtuin 1 (SIRT1), Mitochondrial transcriptional factor A (TFAM) and augmented mitochondrial DNA (mtDNA), NOD like receptor protein 3 (NLRP3) and Caspase 1 was assessed. Rats receiving PQQ and ATS revealed significant decrease in body weights, anthropometric parameter, and adipose tissue vis-à-vis positive control. PQQ alone and with ATS improved glucose tolerance, lipid profile, insulin indices and lowered serum levels of inflammatory cytokines IL-18, IL-1β, TNF-α and IL-6 along with a rise in adiponectin. PQQ supplementation with ATS upregulated the mRNA expression of PGC 1α, SIRT1, TFAM and augmented mtDNA while downregulating inflammatory markers NLRP3 and Caspase 1. PQQ supplementation with atorvastatin holds therapeutic promise to effectively combat mitochondrial dysfunction and chronic low-grade inflammation in obesity.

Markers of inflammation and insulin resistance in dogs before and after weight loss versus lean healthy dogs

ABSTRACT: Chronic low-grade inflammation in obesity is characterized by an increased production of pro-inflammatory cytokines that contribute to insulin resistance. For this study body composition, markers of inflammation and of insulin resistance in dogs before and after weight loss were compared to those of lean dogs. Eleven client-owned obese adult dogs underwent a weight loss program with commercial dry food for weight loss and reached an ideal body condition score (BCS) six months after the beginning of the weight loss program. A Control Group of nine dogs with ideal BCS were selected for the comparison. Shapiro-Wilk test was used to test for normality, Mann Whitney were used for non-normally distributes data, and Student t-test was used for normally distributed parameters. In the Obese Group body fat decreased from 41.6% (30.7-58.6) to 29.1% (18.6-46.3) (P&lt;0.01) and dogs maintained lean body mass throughout the weight loss program (P&gt;0.05). Obese dogs presented higher concentration of fructosamine, triglycerides, insulin, IGF-1 and leptin than the Control Group before weight reduction (P&lt;0.05). Serum concentrations of triglycerides, IL-2, IL-6, TNF-α, insulin, leptin and IGF-1 decreased after weight loss (P&lt;0.01), and these concentrations were similar to the Control Group (P&gt;0.05), except for leptin (P&lt;0.001). No alteration on peptide YY was found. Leptin (r=0.60, P=0.01), fructosamine (r=0.44, P=0.02) and triglycerides (r=0.40, P=0.04) concentrations correlated with the reduction of body fat. Weight loss reduced the concentrations of inflammatory and insulin resistance markers and most parameters became similar to dogs that have always been lean, reinforcing the importance of weight loss in small animal practice.

Enhanced glycolysis and HIF-1\u03b1 activation in adipose tissue macrophages sustains local and systemic interleukin-1\u03b2 production in obesity

During obesity, macrophages infiltrate the visceral adipose tissue and promote inflammation that contributes to type II diabetes. Evidence suggests that the rewiring of cellular metabolism can regulate macrophage function. However, the metabolic programs that characterize adipose tissue macrophages (ATM) in obesity are poorly defined. Here, we demonstrate that ATM from obese mice exhibit metabolic profiles characterized by elevated glycolysis and oxidative phosphorylation, distinct from ATM from lean mice. Increased activation of HIF-1α in ATM of obese visceral adipose tissue resulted in induction of IL-1β and genes in the glycolytic pathway. Using a hypoxia-tracer, we show that HIF-1α nuclear translocation occurred both in hypoxic and non-hypoxic ATM suggesting that both hypoxic and pseudohypoxic stimuli activate HIF-1α and its target genes in ATM during diet-induced obesity. Exposure of macrophages to the saturated fatty acid palmitate increased glycolysis and HIF-1α expression, which culminated in IL-1β induction thereby simulating pseudohypoxia. Using mice with macrophage-specific targeted deletion of HIF-1α, we demonstrate the critical role of HIF-1α-derived from macrophages in regulating ATM accumulation, and local and systemic IL-1β production, but not in modulating systemic metabolic responses. Collectively, our data identify enhanced glycolysis and HIF-1α activation as drivers of low-grade inflammation in obesity.

Perturbation of the Monocyte Compartment in Human Obesity.

Circulating monocytes can be divided into classical (CM), intermediate (IM), and non-classical monocytes (NCM), and the classical monocytes also contain CD56+ monocytes and monocytic myeloid-derived suppressor cells (M-MDSC). The aim of the study was to evaluate the occurrence of the monocyte subpopulations in human obesity. Twenty-seven normal, 23 overweight, and 60 obese individuals (including 17 obese individuals with normal glucose tolerance and 27 with type 2 diabetes) were included into this study. Peripheral blood mononuclear cells were isolated from human blood, and surface markers to identify monocyte subpopulations were analyzed by flow cytometry. Obese individuals had higher numbers of total monocytes, CM, IM, CD56+ monocytes, and M-MDSCs. The number of CM, IM, CD56+ monocytes, and M-MDSCs, correlated positively with body mass index, body fat, waist circumference, triglycerides, C-reactive protein, and HbA1c, and negatively with high-density lipoprotein cholesterol. Individuals with obesity and type 2 diabetes had higher numbers of IM, NCM, and M-MDSCs, whereas those with obesity and impaired glucose tolerance had higher numbers of CD56+ monocytes. In summary, the comprehensive analysis of blood monocytes in human obesity revealed a shift of the monocyte compartment toward pro-inflammatory monocytes which might contribute to the development of low-grade inflammation in obesity, and immune-suppressive monocytes which might contribute to the development of cancer in obesity.

Metabolic endotoxemia promotes adipose dysfunction and inflammation in human obesity

Impaired adipose tissue (AT) lipid handling and inflammation is associated with obesity-related metabolic diseases. Circulating lipopolysaccharides (LPSs) from gut microbiota (metabolic endotoxemia), proposed as a triggering factor for the low-grade inflammation in obesity, might also be responsible for AT dysfunction. Nevertheless, this hypothesis has not been explored in human obesity. To analyze the relationship between metabolic endotoxemia and AT markers for lipogenesis, lipid handling, and inflammation in human obesity, 33 patients with obesity scheduled for surgery were recruited and classified according to their LPS levels. Visceral and subcutaneous AT gene and protein expression were analyzed and adipocyte and AT in vitro assays performed. Subjects with obesity with a high degree of metabolic endotoxemia had lower expression of key genes for AT function and lipogenesis ( SREBP1, FABP4, FASN, and LEP) but higher expression of inflammatory genes in visceral and subcutaneous AT than subjects with low LPS levels. In vitro experiments corroborated that LPS are responsible for adipocyte and AT inflammation and downregulation of PPARG, SCD, FABP4, and LEP expression and LEP secretion. Thus, metabolic endotoxemia influences AT physiology in human obesity by decreasing the expression of factors involved in AT lipid handling and function as well as by increasing inflammation.

Electroacupuncture: A Feasible Sirt1 Promoter Which Modulates Metainflammation in Diet-Induced Obesity Rats

It is generally accepted that metainflammation, a state of chronic and low-grade inflammation in obesity, plays a great role in metabolic disorder like insulin resistance. To gain further insight into the mechanism of metainflammation and find feasible therapy of obesity, diet-induced obesity (DIO) rats model and Electroacupuncture (EA) treatment were established in this trail. The results indicated that rising Lee's index, hyperlipidemia, insulin resistance, and increasing inflammation factors including NF-κB, TNF-α, and Macrophages 1 were determined in DIO rats while EA is exhibiting an effective intervention. Furthermore, to clarify this phenomenon and provide new recognition of alternative medicine for the treatment of metainflammation, we found that EA activating Sirt1 and Sirt1-dependent deacetylation of histone (H3K9) was the key of modulation. It should be noted that, while possible, the activating of Sirt1 could lead to deacetylation of NF-κB also. In this study, the deacetylation of NF-κB depended on higher level of Sirt1 than H3K9, which suggested that the deacetylation via Sirt1 in metainflammation could be specific and programmed.

Exosomes or Microvesicles, a Secreted Subcellular Organelle Contributing to Inflammation and Diabetes.

Type 1 and type 2 diabetes (T1D and T2D) are generally recognized as distinct disease entities based on the mechanism of induction of disease: T1D results from low or no insulin production due to the gradual loss of cells that produce insulin, whereas T2D is generally thought to occur as a result of the body’s development of resistance to insulin. Although the events initiating T1D and T2D might be very different, the progression to diabetes and complications are similar and involve interactions between the immune system and the metabolic system. Notably, chronic inflammation is a shared manifestation of the two types of diabetes (1,2). Recently, secreted microvesicles, particularly exosomes, were suggested to be intermediates linking inflammation to diabetes (3). The cellular origins of the vesicles and the genetic and environmental factors that cause an abnormal production of the vesicles are likely to be central in linking the inflammation to tissue-specific damage. For example, islet mesenchymal stem cells from autoimmune-prone animals were shown to release highly proinflammatory exosomes that contributed to T1D (4), and the low-grade inflammation in obesity may stimulate release of proinflammatory microvesicles and exosomes to accelerate T2D (5,6). “Extracellular vesicles” (EVs) is a collective term for different types of small-sized membrane vesicles or particles that are secreted by cells, including exosomes, microvesicles, apoptotic bodies, and virus-like particles. Figure 1 shows a generalization of their similarities and differences in biogenesis and immune-stimulatory function. There are many reasons that such organelles may be produced, including packaging of paracrine factors for intercellular communications, apoptosis resulting from breakdown of cells, and packaging of material for ingestion and disposal by scavenger cells (7). Viruses too have learned to take advantage of the vesicle biogenesis machinery to hide from immune surveillance to establish infections at immune-privileged sites …

M1 Extra Weight in the Balance: The Role of Macrophages in Obesity

Obesity affects millions of people worldwide and is a complex and multifactorial syndrome. Alterations in eating habits and lifestyle in developed countries increased obesity rates drastically through the past years and also the deaths associated with this condition. The immune system is an important component to maintain adipose tissue homeostasis and also to promote inflammation during obesity. In this mini review, we will briefly describe the main factors that contribute to systemic low-grade inflammation in obesity and lead to insulin resistance.

Elevated adipose tissue expression of CCL19 in obese individuals with or without type-2 diabetes: Its association with metabolic inflammation

Abstract Adipose tissue produces inflammatory molecules considered to be involved in the development of chronic low-grade inflammation in obesity and type 2 diabetes (T2D). The adipose tissue expression of CCL19 or macrophage inflammatory protein (MIP)-3β in obesity is poorly understood. We, therefore, determined CCL19 gene expression in the adipose tissue samples from lean, overweight, and obese individuals with or without T2D. Subcutaneous adipose samples were collected from 58 non-diabetic (ND) (27-obese, 21-overweight, and 10-lean) and 49 T2D (34-obese, 11-overweight, and 4-lean) individuals. Gene expression of CCL19 and other inflammatory markers was determined using real-time RT-PCR. Plasma CRP and adiponectin were measured by ELISA. CCL19 expression was significantly higher in obese compared with lean individuals (ND: P&amp;lt;0.04; T2D: P&amp;lt;0.02). Notably, CCL19 expression was relatively higher in T2D than ND individuals regarding each body mass index (BMI) group. CCL19 expression correlated with BMI (ND: r=026, p=0.04; T2D: r=0.45, P=0.001). In relation to immune markers, CCL19 expression had association with CXCL10, IL-12A, and TLR2 in ND individuals, and with IL-6, IL-1β, TGF-β, TNF-α, TLR9, CCL11 and IRAK-1 in T2D individuals, while it associated with MyD88, CCL5, CCR2, and CRP in both populations. However, CCL19 gene expression associated negatively with adiponectin in ND individuals. With regard to clinical markers, in both populations, CCL19 expression correlated positively with triglycerides, fasting blood glucose, and HbA1C, whereas it had negative association with HDL cholesterol. These data support that increased adipose tissue expression of CCL19 may represent an immune signature of metabolic inflammation.

WISP1 promotes non-alcoholic fatty liver disease and skeletal muscle insulin resistance via TLR4/JNK signaling.

Wnt1-inducible signaling pathway protein-1 (WISP1) is a Cyr61/CTGF/NOV (CCN) family matricellular protein involved in adipogenesis and low-grade inflammation in obesity. However, the roles of WISP1 in hepatic steatosis and insulin resistance in skeletal muscle remain elusive. Mouse primary hepatocytes and differentiated mouse skeletal muscle cells (C2C12) were treated with various concentrations of WISP1 and the functions and signaling pathways were analyzed by Western blot analysis. In vivo transfection for WISP1 knockdown was also performed to examine the effects of WISP1 on hepatic steatosis and skeletal muscle insulin resistance. Knockdown of WISP1 in high-fat diet-fed C57BL/6 mice significantly reduced (0.45-0.5%; p < 0.05) inflammation and JNK phosphorylation (45-50%; P < 0.01) and attenuated hepatic steatosis (approximately 55%; p < 0.001) and skeletal muscle insulin resistance (30-40%; p < 0.05). Treatment with WISP1 significantly induced inflammation (hepatocytes: approximately 500%; p < 0.01, C2C12 cells: approximately 500%; p < 0.01) and JNK phosphorylation (hepatocytes: approximately 200%; p < 0.01, C2C12 cells: approximately 280%; p < 0.01) in mouse primary hepatocytes and C2C12 mouse skeletal muscle cells. Moreover, it increased lipogenesis-associated gene expression (200-300%; p < 0.01) and accumulation of triglycerides (approximately 320%; p < 0.01) in hepatocytes, and suppressed insulin signaling (approximately 50%; p < 0.01) in C2C12 cells. These WISP1-induced effects were significantly abrogated in NFκB-, JNK-, and TLR4-knockdown hepatocytes (p < 0.05) and C2C12 cells (p < 0.05). These results indicate that WISP1 contributes to hepatic steatosis and skeletal muscle insulin resistance through a TLR4-activated inflammation/JNK signaling pathway and could be a useful therapeutic target for treatment of non-alcoholic fatty liver disease and type 2 diabetes.

MiR27a Promotes the Development of Macrophage-like Characteristics in 3T3-L1 Preadipocytes.

Recruitment and polarization of classically activated (M1) macrophages within adipose tissue contribute to chronic low-grade inflammation in obesity. Adipose tissue precursor cells exhibit the capacity to develop macrophage-like characteristics and adipocyte-derived miR27a is known to promote reprogramming of somatic cells. It was unknown whether exogenous addition of miR27a promote the development of macrophage-like characteristics of adipose precursor cells. We examined macrophage surface antigen, phagocytosis and migration ability in 3T3-L1 preadipocytes transfected with miR27a mimics. Transfection of 3T3-L1 preadipocytes with miR27a mimics increased phagocytosis and migration and increased the number of cells expressing the macrophage makers F4/80 and MHC compared to controls. M2 and CD206 macrophage markers were unaltered. In addition, transfection of 3T3-L1 preadipocytes with miR27a mimics reduced PPARγ expression, activated NF-κB and promoted secretion of the inflammatory cytokines MCP-1, TNF-α and IL-1β compared to controls. The level of anti-inflammatory factors Arg-1, IL-10, Ym1 and Fizz1 were unaltered. Secretion of miR27a was increased in conditioned medium prepared from palmitic acid-treated differentiated 3T3-L1 adipocytes compared to controls. Incubation of 3T3-L1 preadipocytes with this conditioned medium increased phagocytosis and migration compared to controls. Finally, conditioned medium prepared from differentiated 3T3-L1 adipocytes transfection with miR27a inhibitors reduced phagocytosis and migration in 3T3-L1 preadipocytes compared to controls. The data indicate that PPARγ agonists may reverse the activation of NF-κB pathway mediated by miR27a overexpression and reduce phagocytosis and migration of adipose precursor cells. In addition, miR27a may promote the development of macrophage-like characteristics in 3T3-L1 preadipocytes.

Metformin improves obesity-associated inflammation by altering macrophages polarization

Obesity is reported to be a chronic low-grade inflammatory state. Adipose tissue macrophages play a key role in obesity-related inflammation. Metformin, the most widely used anti-diabetic drug, has recently been reported to have an effect on inflammation, but the mechanism is poorly understood. This study aims to investigate how metformin works on chronic low-grade inflammation in obesity and whether the mechanism underlying it is associated with macrophage polarization. Metformin was administered for 7 weeks to high fat-fed C57/6J male mice in vivo. Metformin, compound C (an AMPK inhibitor) and AICAR (an AMPK activator) were used for the in vitro intervention. The gene expression of macrophages markers was examined. Pro-inflammatory cytokines IL-6 and TNF-α were tested by ELISA. The macrophage subsets were analyzed by flow cytometry. In vivo, we discovered that metformin not only decreased the serum level of the pro-inflammatory cytokines IL-6 and TNF-α but also lowered the expression of the M1 macrophage markers CD11c and MCP-1 in adipose tissue. In vitro, metformin reduced the secretion of IL-6 and TNF-α in palmitate-stimulated RAW264.7 macrophages, while compound C treatment blocked the effect of metformin. Moreover, treatment with metformin and AICAR decreased the proportion of M1 macrophages and increased the proportion of M2 macrophages, as analyzed by flow cytometry, in palmitate-stimulated BMDMs. In addition, the effect of AICAR on macrophage polarization was stronger than that of metformin. These results suggest that metformin improves low-grade inflammation in obesity and modulates macrophage polarization to an anti-inflammatory, M2 phenotype partly via the activation of AMPK.

LPS-Induced Low-Grade Inflammation Increases Hypothalamic JNK Expression and Causes Central Insulin Resistance Irrespective of Body Weight Changes.

Metabolic endotoxemia contributes to low-grade inflammation in obesity, which causes insulin resistance due to the activation of intracellular proinflammatory pathways, such as the c-Jun N-terminal Kinase (JNK) cascade in the hypothalamus and other tissues. However, it remains unclear whether the proinflammatory process precedes insulin resistance or it appears because of the development of obesity. Hypothalamic low-grade inflammation was induced by prolonged lipopolysaccharide (LPS) exposure to investigate if central insulin resistance is induced by an inflammatory stimulus regardless of obesity. Male Wistar rats were treated with single (1 LPS) or repeated injections (6 LPS) of LPS (100 μg/kg, IP) to evaluate the phosphorylation of the insulin receptor substrate-1 (IRS1), Protein kinase B (AKT), and JNK in the hypothalamus. Single LPS increased the expression of pIRS1, pAKT, and pJNK, whereas the repeated LPS treatment failed to recruit pIRS1 and pAKT. The 6 LPS treated rats showed increased total JNK and pJNK. The 6 LPS rats became unresponsive to the hypophagic effect induced by central insulin administration (12 μM/5 μL, ICV). Prolonged exposure to LPS (24 h) impaired the insulin-induced AKT phosphorylation and the translocation of the transcription factor forkhead box protein O1 (FoxO1) from the nucleus to the cytoplasm of the cultured hypothalamic GT1-7 cells. Central administration of the JNK inhibitor (20 μM/5 μL, ICV) restored the ability of insulin to phosphorylate IRS1 and AKT in 6 LPS rats. The present data suggest that an increased JNK activity in the hypothalamus underlies the development of insulin resistance during prolonged exposure to endotoxins. Our study reveals that weight gain is not mandatory for the development of hypothalamic insulin resistance and the blockade of proinflammatory pathways could be useful for restoring the insulin signaling during prolonged low-grade inflammation as seen in obesity.