Adipose Tissue Macrophage Polarization Research Articles

Gut dysbiosis contributes to SCFAs reduction-associated adipose tissue macrophage polarization in gestational diabetes mellitus

AimsThe prevalence of gestational diabetes mellitus (GDM) has spurred investigations into various interconnected factors, among which gut dysbiosis is notably prominent. Although gut dysbiosis is strongly associated with GDM, the specific role of the gut microbiome in the pathogenesis of GDM remains unknown. This study aims to explore the pathogenesis of GDM from gut microbiota. Materials and methodsIn our study, we constructed two GDM mice models: one induced by a high-fat diet (HFD) and the other through fecal microbiota transplantation (FMT) from GDM patients. In vitro, we used a co-culture system of RAW264.7 and 3T3-L1 adipocytes. Key findingsWe induced a GDM-like state in pregnant mice by FMT from GDM patients, which was consistent with the HFD model. A potential mechanism identified involves the diminished abundance of SCFA-producing microbiota, which reduces SCFAs, particularly propionic acid and butyric acid. In vitro, butyric and propionic acids were observed to alleviate LPS-induced TLR4-NF-κB activation, thereby reducing inflammation levels and inhibiting adipose insulin resistance via the PI3K/AKT signaling pathway. This reduction appears to trigger the polarization of adipose tissue macrophages toward M1 and promote insulin resistance in adipose tissue. SignificanceOur study fills this knowledge gap by finding that alterations in gut microbiota have an independent impact on hyperglycemia and insulin resistance in the GDM state. In vivo and in vitro, gut dysbiosis is linked to adipose tissue inflammation and insulin resistance via the bacterial product SCFAs in the GDM state, providing new insights into the pathogenesis of GDM.

Adipose tissue macrophages secrete small extracellular vesicles that mediate rosiglitazone-induced insulin sensitization.

The obesity epidemic continues to worsen worldwide, driving metabolic and chronic inflammatory diseases. Thiazolidinediones, such as rosiglitazone (Rosi), are PPARγ agonists that promote 'M2-like' adipose tissue macrophage (ATM) polarization and cause insulin sensitization. As ATM-derived small extracellular vesicles (ATM-sEVs) from lean mice are known to increase insulin sensitivity, we assessed the metabolic effects of ATM-sEVs from Rosi-treated obese male mice (Rosi-ATM-sEVs). Here we show that Rosi leads to improved glucose and insulin tolerance, transcriptional repolarization of ATMs and increased sEV secretion. Administration of Rosi-ATM-sEVs rescues obesity-induced glucose intolerance and insulin sensitivity in vivo without the known thiazolidinedione-induced adverse effects of weight gain or haemodilution. Rosi-ATM-sEVs directly increase insulin sensitivity in adipocytes, myotubes and primary mouse and human hepatocytes. Additionally, we demonstrate that the miRNAs within Rosi-ATM-sEVs, primarily miR-690, are responsible for these beneficial metabolic effects. Thus, using ATM-sEVs with specific miRNAs may provide a therapeutic path to induce insulin sensitization.

IL-6 signaling drives self-renewal and alternative activation of adipose tissue macrophages.

Obesity is associated with chronic low-grade inflammation of adipose tissue (AT) and an increase of AT macrophages (ATMs) that is linked to the onset of type 2 diabetes. We have recently shown that neutralization of interleukin (IL)-6 in obese AT organ cultures inhibits proliferation of ATMs, which occurs preferentially in alternatively activated macrophage phenotype. In this study, we investigated AT biology and the metabolic phenotype of mice with myeloid cell-specific IL-6Rα deficiency (Il6ra Δmyel) after normal chow and 20 weeks of high-fat diet focusing on AT inflammation, ATM polarization and proliferation. Using organotypical AT culture and bone marrow derived macrophages (BMDMs) of IL-4Rα knockout mice (Il4ra -/-) we studied IL-6 signaling. Obese Il6ra Δmyel mice exhibited no differences in insulin sensitivity or histological markers of AT inflammation. Notably, we found a reduction of ATMs expressing the mannose receptor 1 (CD206), as well as a decrease of the proliferation marker Ki67 in ATMs of Il6ra Δmyel mice. Importantly, organotypical AT culture and BMDM data of Il4ra -/- mice revealed that IL-6 mediates a shift towards the M2 phenotype independent from the IL-6/IL-4Rα axis. Our results demonstrate IL-4Rα-independent anti-inflammatory effects of IL-6 on macrophages and the ability of IL-6 to maintain proliferation rates in obese AT.

Chondroitin Sulfate-Derived Micelles for Adipose Tissue-Targeted Delivery of Celastrol and Phenformin to Enhance Obesity Treatment.

Adipose tissue macrophages (ATMs) are crucial in maintaining a low-grade inflammatory microenvironment in adipose tissues (ATs). Modulating ATM polarization to attenuate inflammation represents a potential strategy for treating obesity with insulin resistance. This study develops a combination therapy of celastrol (CLT) and phenformin (PHE) using chondroitin sulfate-derived micelles. Specifically, CLT-loaded 4-aminophenylboronic acid pinacol ester-modified chondroitin sulfate micelle (CS-PBE/CLT) and chondroitin sulfate-phenformin conjugate micelles (CS-PHE) were synthesized, which were shown to actively target ATs through CD44-mediated pathways. Furthermore, the dual micellar systems significantly reduced inflammation and lipid accumulation via protein quantification and Oil Red O staining. In preliminary in vivo studies, we performed H&E staining, immunohistochemical staining, insulin tolerance test, and glucose tolerance test, and the results showed that the combination therapy using CS-PBE/CLT and CS-PHE micelles significantly reduced the average body weight, white adipose tissue mass, and liver mass of high-fat diet-fed mice while improving their systemic glucose homeostasis. Overall, this combination therapy presents a promising alternative to current treatment options for diet-induced obesity.

Adipose Tissue Macrophage Polarization Is Altered during Recovery after Exercise: A Large-Scale Flow Cytometric Study.

We performed a large-scale flow cytometric analysis to determine whether M1 macrophage (M1Ø) and M2 macrophage (M2Ø) polarization in white adipose tissue (WAT) was altered immediately after exercise. Additionally, we comprehensively investigated the effects of obesity, exercise intensity, and recovery time on macrophage polarization in WAT. A single exercise bout of various intensities (ND, non-exercise control; -LIE, low-intensity exercise; -MIE, mid-intensity exercise; -HIE, high-intensity exercise) was performed by normal mice (ND) and obese mice (HFD). To confirm differences in M1Ø/M2Ø polarization in WAT based on the recovery time after a single exercise bout, WAT was acquired at 2 h, 24 h, and 48 h after exercise (total n = 168, 7 mice × 4 groups × 2 diets × 3 recovery time). The harvested WAT was immediately analyzed by flow cytometry, and macrophages were fluorescently labeled using F4/80, as well as M1Ø with CD11c and M2Øs with CD206. After a single bout of exercise, the M2Ø/M1Ø polarization ratio of WAT increases in both normal and obese mice, but differences vary depending on recovery time and intensity. Regardless of obesity, our findings showed that there could be a transient increase in M1Ø in WAT over a short recovery time (24 h) post-exercise (in ND-MIE, ND-HIE, and HFD-HIE). Furthermore, it was observed that the greater the exercise intensity in obese mice, the more effective the induction of M2Ø polarization immediately after exercise, as well as the maintenance of high M2Ø polarization, even after a prolonged recovery time.

Inhibition of soluble epoxide hydrolase relieves adipose inflammation via modulating M1/M2 macrophage polarization to alleviate airway inflammation and hyperresponsiveness in obese asthma

Obesityincreasestheriskofasthma and tends to enhance the asthma severity, however, its mechanism is not fully elucidated. The expansion of adipose tissue in obesity is accompanied by the accumulation of adiposetissue macrophages (ATMs) that could contribute to alow-gradeinflammationstate. In this study, we researched the regulatory role of soluble epoxide hydrolase (sEH) on ATMs-mediated inflammation in obese asthma. A mouse model of obese asthma that induced by high-fat diet (HFD) feeding and Ovalbumin (OVA) sensitization was employed to investigate the effects of AUDA, a sEH inhibitor (sEHi), on airway inflammation, airway hyperresponsivenesss (AHR) and pulmonary pathological changes. In addition to alleviating the key features of asthma in obese mice, we confirmed that AUDA reduced the expression of pro-inflammatory factor, such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumornecrosisfactor-α (TNF-α) in adipose tissue and serum. Moreover, AUDA could remarkedly reduce Lipopolysaccharide (LPS)-elevated IL-1β, IL-6 and TNF-α in RAW264.7 macrophage cells. Mechanistically, AUDA effectively reduced inflammation in adipose tissue, resulting in reduced systemic inflammation, by inhibiting M1-type macrophage polarization and promoting M2-type macrophage polarization. These processes were found to act through ERK1/2 signaling pathway. Herein, we proved that inhibition of sEH expression helped to mitigate multiple parameters of obese asthma by regulating the balance of M1/M2 macrophage polarization in adipose tissue.

Thromboxane A2/thromboxane A2 receptor axis facilitates hepatic insulin resistance and steatosis through endoplasmic reticulum stress in non-alcoholic fatty liver disease.

Defective insulin signalling and dysfunction of the endoplasmic reticulum (ER), driven by excessive lipid accumulation in the liver, is a characteristic feature in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Thromboxane A2 (TXA2 ), an arachidonic acid metabolite, is significantly elevated in obesity and plays a crucial role in hepatic gluconeogenesis and adipose tissue macrophage polarization. However, the role of liver TXA2 /TP receptors in insulin resistance and lipid metabolism is largely unknown. TP receptor knockout (TP-/- ) mice were generated and fed a high-fat diet for 16 weeks. Insulin sensitivity, ER stress responses and hepatic lipid accumulation were assessed. Furthermore, we used primary hepatocytes to dissect the mechanisms by which the TXA2 /TP receptor axis regulates insulin signalling and hepatocyte lipogenesis. TXA2 was increased in diet-induced obese mice, and depletion of TP receptors in adult mice improved systemic insulin resistance and hepatic steatosis. Mechanistically, we found that the TXA2 /TP receptor axis disrupts insulin signalling by activating the Ca2+ /calcium calmodulin-dependent kinase II γ (CaMKIIγ)-protein kinase RNA-like endoplasmic reticulum kinase (PERK)-C/EBP homologous protein (Chop)-tribbles-like protein 3 (TRB3) axis in hepatocytes. In addition, our results revealed that the TXA2 /TP receptor axis directly promoted lipogenesis in primary hepatocytes and contributed to Kupffer cell inflammation. The TXA2 /TP receptor axis facilitates insulin resistance through Ca2+ /CaMKIIγ to activate PERK-Chop-TRB3 signalling. Inhibition of hepatocyte TP receptors improved hepatic steatosis and inflammation. The TP receptor is a new therapeutic target for NAFLD and metabolic syndrome.

ABHD6 suppression promotes anti-inflammatory polarization of adipose tissue macrophages via 2-monoacylglycerol/PPAR signaling in obese mice

ObjectivePro-inflammatory polarization of adipose tissue macrophages (ATMs) plays a critical role in the pathogenesis of obesity-associated chronic inflammation. However, little is known about the role of lipids in the regulation of ATMs polarity and inflammation in response to metabolic stress. Deletion of α/β-hydrolase domain-containing 6 (ABHD6), a monoacylglycerol (MAG) hydrolase, has been shown to protect against diet-induced obesity and insulin resistance. MethodsHere we investigated the immunometabolic role of macrophage ABHD6 in response to nutrient excess using whole-body ABHD6-KO mice and human and murine macrophage cell-lines treated with KT203, a selective and potent pharmacological ABHD6 inhibitor. ResultsKO mice on high-fat diet showed lower susceptibility to systemic diet-induced inflammation. Moreover, in the setting of overnutrition, stromal vascular cells from gonadal fat of KO vs. control mice contained lower number of M1 macrophages and exhibited enhanced levels of metabolically activated macrophages (MMe) and M2 markers, oxygen consumption, and interleukin-6 (IL-6) release. Likewise, under in vitro nutri-stress condition, inhibition of ABHD6 in MMe-polarized macrophages attenuated the expression and release of pro-inflammatory cytokines and M1 markers and induced the upregulation of lipid metabolism genes. ABHD6-inhibited MMe macrophages showed elevated levels of peroxisome proliferator-activated receptors (PPARs) and 2-MAG species. Notably, among different MAG species, only 2-MAG treatment led to increased levels of PPAR target genes in MMe macrophages. ConclusionsCollectively, our findings identify ABHD6 as a key component of pro-inflammatory macrophage activation in response to excess nutrition and implicate an endogenous macrophage lipolysis/ABHD6/2-MAG/PPARs cascade, as a lipid signaling and immunometabolic pathway, which favors the anti-inflammatory polarization of ATMs in obesity.

Plasma Exosomes Aggravate Acute Pancreatitis by Promoting M1 Polarization of Adipose Tissue Macrophages in Obesity-Related Severe Acute Pancreatitis.

Obesity may be a risk factor for severe acute pancreatitis (SAP). However, its precise mechanism is not yet fully understood. We fed rats with a standard laboratory diet (SLD) and a high-fat diet (HFD). SAP model rats were established by retrograde injection of sodium taurocholate. Serum non-esterified fatty acids (NEFAs), lipase (LPS), and myeloperoxidase (MPO) were measured, as were adipose IL-1, IL-6, IL-10, and TNF-α levels. HE staining was performed to determine the severity of pancreatitis. Serum exosomes were extracted from rats with obesity-related SAP, verified by transmission electron microscopy (TEM) and western blot analysis, and co-cultured with THP-1 cells. Flow cytometry was used to analyze the M1 and M2 phenotypes of macrophages in adipose tissues and THP-1 cells. Q-PCR was used to analyze the levels of IL-1, IL-6, IL-10, and TNF-α in each group of cells. The body weight and serum NEFA concentrations of rats in the HFD group were significantly higher than those in the SLD group. Adipose tissue macrophages in the HFD group exhibited a higher percentage of the M1 type than those in the SLD group. The severity of pancreatitis were significantly increased in the HFD + SAP group. Pro-inflammatory macrophages and cytokines were significantly higher in the HFD + SAP group and THP-1 cells co-cultured with serum exosomes extracted from rats with obesity-related SAP. Obesity might worsen the severity of pancreatitis by amplifying the immune response and activating M1 polarization in adipose tissue macrophages via serum exosomes in rats of obesity-related SAP. In our study, we isolated exosomes from the serum of mice with obesity-related SAP. After inducing THP-1 cells to become M0-typed macrophages, we co-cultured the cells with exosomes and observed that exosomes from obesity-related SAP increased the proportion of M1-typed macrophages and promoted the release of pro-inflammatory factors such as IL-1, IL-6, and TNF. Therefore, obesity might worsen the severity of pancreatitis by amplifying the immune response and activating M1 polarization in adipose tissue macrophages via serum exosomes in rats of obesity-related SAP.

22-LB: MiRNA Profiling of Exosomes Derived from Perivascular Adipocyte Tissue in Type 2 Diabetic Mice

Background: Exosomes (EXs), a major type of extracellular vesicles, are emerging as a novel type of intercellular communicators. MicroRNAs (miRs) are one of the major executors of EXs. The previous study shows that lean and obesity adipocyte tissue EXs could elicit different effects in response to insulin sensitivity, the underlying mechanism is related to their carried miRs. Given EX cargoes and function vary on their cellular status, we speculate the miR profiling of EXs derived from the perivascular adipose tissue (PVAT) is altered in diabetic conditions. Methods: EXs were isolated from the PVAT tissue of type 2 diabetic db/db and control db/c mice. EX size and concentration were analyzed by nanoparticle tracking analysis. The miR profiling of PVAT-EXs was analyzed by mmu-miR miRome profiling kit. The miRs of interest were further validated by qRT-PCR. Results: 1) The PVAT-EXs level was higher in diabetic db/db mice than that in non-diabetic db/c mice; 2) In db/db mice, exosomal miRs profile was changed. The exosomal miRs, miR-223, miR-181a, miR-146a, miR-34a, and miR-210, were either down-regulated or up-regulated > 3-fold when comparing that in db/c mice. Among these candidate miRs, miR-181a, miR-223, miR-210, and miR-146a might be involved in modulating adipose tissue inflammation and/or vascular function. MiR-34a could participate in white adipose tissue browning, macrophage polarization, and glucose tolerance. Conclusion: Our data have demonstrated that the miR profiling of PVAT-derived EXs is changed in type 2 diabetic conditions, which suggests the functions of these EXs might be altered in diabetic conditions. Disclosure S. Chen: None. V. Polaki: None. J. Bihl: None. J. Wang: None.

Regulatory mechanisms of macrophage polarization in adipose tissue.

In adipose tissue, macrophages are the most abundant immune cells with high heterogeneity and plasticity. Depending on environmental cues and molecular mediators, adipose tissue macrophages (ATMs) can be polarized into pro- or anti-inflammatory cells. In the state of obesity, ATMs switch from the M2 polarized state to the M1 state, which contributes to chronic inflammation, thereby promoting the pathogenic progression of obesity and other metabolic diseases. Recent studies show that multiple ATM subpopulations cluster separately from the M1 or M2 polarized state. Various factors are related to ATM polarization, including cytokines, hormones, metabolites and transcription factors. Here, we discuss our current understanding of the potential regulatory mechanisms underlying ATM polarization induced by autocrine and paracrine factors. A better understanding of how ATMs polarize may provide new therapeutic strategies for obesity-related diseases.

Effects of Melatonin on Fat Graft Retention Through Browning of Adipose Tissue and Alternative Macrophage Polarization.

Melatonin is a widely used drug that can affect adipocyte inflammation, resulting in adipose tissue browning. Inducing the browning of white fat and changing the inflammatory microenvironment of early transplanted fat have positive effects on the retention rate of fat grafts. This study aimed to evaluate the effects of melatonin on fat graft retention, determine whether it is related to adipose tissue browning and the inflammatory microenvironment, and explore the underlying mechanisms. A C57BL/6 mice fat transplantation model was established. The mice were divided into a control group (ethanol), a high-dose group (40 mg/kg/day melatonin), a medium-dose group (20 mg/kg/day melatonin), and a low-dose group (10 mg/kg/day melatonin). They were also given oral gavage treatment for 2 weeks. The grafted fat was collected 2, 4, and 12 weeks after treatment. The medium-dose and high-dose melatonin groups had significantly higher fat graft retention rates than the control group at 12 weeks. The medium-dose melatonin group had smaller multilocular adipocytes, which enhanced the expression of uncoupling protein 1 and increased neovascularization in the grafted fat. The medium-dose group also had a higher distribution of M2 macrophages. These findings suggest that melatonin administration can improve the retention of fat grafts through polarization of macrophages toward the anti-inflammatory type and induction of adipose tissue browning. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Large yellow tea polysaccharides ameliorate obesity-associated metabolic syndrome by promoting M2 polarization of adipose tissue macrophages.

Obesity-induced metabolic syndrome is strongly associated with infiltrated adipose tissue macrophages (ATMs). Large yellow tea, a traditional functional beverage in China, has been shown to possess anti-obesity effects. However, the effect of large yellow tea polysaccharides (LYPs) against obesity-associated metabolic syndrome and their underlying mechanisms remain unclear and must be extensively investigated. In this study, we investigated the ameliorative effect of LYPs on metabolic syndrome using a high-fat diet (HFD)-induced obese mouse model. Our results indicated that LYPs significantly alleviated weight gain, dyslipidemia, glucose intolerance, and insulin resistance. Moreover, LYPs restored the homeostasis of energy metabolism and pancreatic β-cell function. Notably, LYPs promoted M2 polarization of ATMs by regulating the expression of genes and specific cytokines involved in the assembly and secretion of M2 polarization. The improved metabolic syndrome of LYPs might be associated with the modulation of macrophage polarization. These findings suggest that LYPs might be a novel potential therapeutic agent to prevent or treat HFD-induced metabolic disorders by regulating M2 polarization.

MiR-210-3p Promotes Obesity-Induced Adipose Tissue Inflammation and Insulin Resistance by Targeting SOCS1-Mediated NF-κB Pathway.

Under the condition of chronic obesity, an increased level of free fatty acids along with low oxygen tension in the adipose tissue creates a pathophysiological adipose tissue microenvironment (ATenv), leading to the impairment of adipocyte function and insulin resistance. Here, we found the synergistic effect of hypoxia and lipid (H + L) surge in fostering adipose tissue macrophage (ATM) inflammation and polarization. ATenv significantly increased miR-210-3p expression in ATMs which promotes NF-κB activation-dependent proinflammatory cytokine expression along with the downregulation of anti-inflammatory cytokine expression. Interestingly, delivery of miR-210-3p mimic significantly increased macrophage inflammation in the absence of H + L co-stimulation, while miR-210-3p inhibitor notably compromised H + L-induced macrophage inflammation through increased production of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of the NF-κB inflammatory signaling pathway. Mechanistically, miR-210 directly binds to the 3'-UTR of SOCS1 mRNA and silences its expression, thus preventing proteasomal degradation of NF-κB p65. Direct delivery of anti-miR-210-3p LNA in the ATenv markedly rescued mice from obesity-induced adipose tissue inflammation and insulin resistance. Thus, miR-210-3p inhibition in ATMs could serve as a novel therapeutic strategy for managing obesity-induced type 2 diabetes.

Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2

Adipose tissue macrophage (ATM) inflammation is involved with meta-inflammation and pathology of metabolic complications. Here we report that in adipocytes, elevated lactate production, previously regarded as the waste product of glycolysis, serves as a danger signal to promote ATM polarization to an inflammatory state in the context of obesity. Adipocyte-selective deletion of lactate dehydrogenase A (Ldha), the enzyme converting pyruvate to lactate, protects mice from obesity-associated glucose intolerance and insulin resistance, accompanied by a lower percentage of inflammatory ATM and reduced production of pro-inflammatory cytokines such as interleukin 1β (IL-1β). Mechanistically, lactate, at its physiological concentration, fosters the activation of inflammatory macrophages by directly binding to the catalytic domain of prolyl hydroxylase domain-containing 2 (PHD2) in a competitive manner with α-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1α). Lactate-induced IL-1β was abolished in PHD2-deficient macrophages. Human adipose lactate level is positively linked with local inflammatory features and insulin resistance index independent of the body mass index (BMI). Our study shows a critical function of adipocyte-derived lactate in promoting the pro-inflammatory microenvironment in adipose and identifies PHD2 as a direct sensor of lactate, which functions to connect chronic inflammation and energy metabolism.

Adipocytes-Derived Exosomal microRNA-1224 Inhibits M2 Macrophage Polarization in Obesity-Induced Adipose Tissue Inflammation via MSI2-Mediated Wnt/β-Catenin Axis.

Phenotypic switch of macrophage polarization in adipose tissue has been associated with obesity-induced adipose tissue inflammation (OATI). Therefore, this study aims to explore the possible mechanism of adipocytes-derived exosomes (ADEs) carrying microRNA-1224 (miR-1224) in M2 macrophage polarization of OATI. miR-1224-knockout (miR-1224-KO) mice for this study, and isolated primary adipocytes from high-fat diet (HFD) or normal diet (SD)-fed mice are developed. ADEs are extracted and cocultured with bone marrow-derived macrophages (BMDMs). The macrophagic crown-like structures (CLS) and M1 and M2 phenotype macrophages in epididymal white adipose tissue (epiWAT) are observed by immunohistochemistry and flow cytometry. The obtained data indicate that miR-1224 is highly expressed in adipose tissues and adipocytes of obese mice. miR-1224 knockout decreases CLS number and increases M2 macrophages polarization in epiWAT. In addition, miR-1224 can be transferred to BMDMs via ADEs, which targeted musashi RNA binding protein 2 (MSI2) expression and inactivated Wnt/β-catenin pathway, inhibiting macrophage M2 polarization and promoting inflammatory factor release. Exosomal miR-1224 derived by adipocytes targets MSI2 and blocks the Wnt/β-catenin pathway, which inhibits macrophage M2 polarization and promotes inflammatory factor release, ultimately promoting OATI.

Cellular and Molecular Mechanisms and Effects of Berberine on Obesity-Induced Inflammation.

Obesity represents chronic low-grade inflammation that precipitates type 2 diabetes, cardiovascular disease, and cancer. Berberine (BBR) has been reported to exert anti-obesity and anti-inflammatory benefits. We aimed to demonstrate the underlying immune-modulating mechanisms of anti-obesity effects of BBR. First, we performed in silico study to identify therapeutic targets, describe potential pathways, and simulate BBR docking at M1 and M2 adipose tissue macrophages (ATMs), tumor necrosis factor-α (TNF-α), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, and C-X-C motif chemokine receptor 4 (CXCR4). Next, in vivo, we divided 20 C58BL/6 mice into four groups: normal chow, control (high fat diet (HFD)), HFD + BBR 100 mg/kg, and HFD + metformin (MET) 200 mg/kg. We evaluated body weight, organ weight, fat area in tissues, oral glucose and fat tolerance tests, HOMA-IR, serum lipids levels, population changes in ATMs, M1 and M2 subsets, and gene expression of TNF-α, CCL2, CCL3, CCL5, and CXCR4. BBR significantly reduced body weight, adipocyte size, fat deposition in the liver, HOMA-IR, triglycerides, free fatty acids, ATM infiltration, all assessed gene expression, and enhanced the CD206+ M2 ATMs population. In conclusion, BBR treats obesity and its associated metabolic dysfunctions, by modulating ATM recruitment and polarization via chemotaxis inhibition.

Macrophage-Specific Connexin 43 Knockout Protects Mice from Obesity-Induced Inflammation and Metabolic Dysfunction.

Adipose tissue macrophages are a major immune cell type contributing to homeostatic maintenance and pathological adipose tissue remodeling. However, the mechanisms underlying macrophage recruitment and polarization in adipose tissue during obesity remain poorly understood. Previous studies have suggested that the gap junctional protein, connexin 43 (Cx43), plays a critical role in macrophage activation and phagocytosis. Herein, we investigated the macrophage-specific roles of Cx43 in high fat diet (HFD)-induced pathological remodeling of adipose tissue. Expression levels of Cx43 were upregulated in macrophages co-cultured with dying adipocytes in vitro, as well as in macrophages associated with dying adipocytes in the adipose tissue of HFD-fed mice. Cx43 knockdown reduced lipopolysaccharide (LPS)-induced ATP release from macrophages and decreased inflammatory responses of macrophages co-cultured with dying adipocytes. Based on global gene expression profiling, macrophage-specific Cx43-knockout (Cx43-MKO) mice were resistant to HFD-induced inflammatory responses in adipose tissue, potentially via P2X7-mediated signaling pathways. Cx43-MKO mice exhibited reduced HFD-induced macrophage recruitment in adipose tissue. Moreover, Cx43-MKO mice showed reduced inflammasome activation in adipose tissues and improved glucose tolerance. Collectively, these findings demonstrate that Cx43 expression in macrophages facilitates inflammasome activation, which, in turn, contributes to HFD-induced metabolic dysfunction.

The Roles of Adipose Tissue Macrophages in Human Disease.

Macrophages are a population of immune cells functioning in antigen presentation and inflammatory response. Research has demonstrated that macrophages belong to a cell lineage with strong plasticity and heterogeneity and can be polarized into different phenotypes under different microenvironments or stimuli. Many macrophages can be recruited by various cytokines secreted by adipose tissue. The recruited macrophages further secrete various inflammatory factors to act on adipocytes, and the interaction between the two leads to chronic inflammation. Previous studies have indicated that adipose tissue macrophages (ATMs) are closely related to metabolic diseases like obesity and diabetes. Here, we will not only conclude the current progress of factors affecting the polarization of adipose tissue macrophages but also elucidate the relationship between ATMs and human diseases. Furthermore, we will highlight its potential in preventing and treating metabolic diseases as immunotherapy targets.

The Effects of Chrysanthemum morifolium Flower Extract on Obesity-Induced Inflammation and Muscle AMPK/SIRT1 Activities in Obese Rats

ObjectivesThe objective of this study is to investigate the effects of hot water extract of Chrysanthemum morifolium Ramat flower (CE) on obesity-induced inflammation and skeletal muscle mitochondrial function in high-fat diet fed rats. MethodsMale Sprague-Dawley rats (3-week-old) were randomly divided into 4 groups, and fed with a normal diet (NOR), high fat diet (HF), HF containing 0.2% CE (CEL) or 0.4% CE (CEH) for 13 weeks. ResultsCE reduced body weight and total white adipose tissue weights. The levels of serum triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) significantly reduced in the CEL and CEH groups compared to the HF group. In white adipose tissue, CE attenuated HF-induced adipose tissue macrophage (ATM) infiltration and down-regulated F4/80 mRNA expression compared to the HF group. In addition, CE down-regulated the mRNA levels involved in inflammation and ATM polarization, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), monocyte chemoattracted protein-1 (MCP1), inducible nitric oxide synthase (iNOS), and cluster of differentiation 11c (CD11c) compared to the HF group. On the other hand, gene expression of arginase 1 (Arg1), a M2 macrophage marker was significantly up-regulated in the CEL and CEH groups compared to the HF group. Nuclear factor-kappa B (NF-κB) activities and serum nitric oxide (NO) concentrations were significantly decreased by CE supplementation. In skeletal muscle, mitochondrial size and mitochondrial DNA (mtDNA) content were significantly increased in the CEL and CEH groups compared to the HF group. CE supplementation were also up-regulated the mRNA expression related to mitochondrial function, including sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and carnitine palmitoyltransferase 1β (CPT-1β). Furthermore, activities of AMP-activated protein kinase (AMPK) and SIRT1 were increased by CE supplementation. ConclusionsThese results suggested that CE attenuates obesity-induced inflammation via regulating M1/M2 macrophage and increases the muscle mitochondria content and AMPK/SIRT1 activities. Funding SourcesThis research was supported by the BK21 FOUR (Fostering Outstanding Universities for Research) funded by the Ministry of Education (MOE, Korea) and National Research Foundation of Korea (NRF).