Obesity-induced Adipose Tissue Inflammation Research Articles

The adipocyte apolipoprotein M is negatively associated with inflammation

Obesity is associated with the development of a local adipose tissue (AT) and systemic inflammation. Most adipokines are upregulated with obesity and have pro-inflammatory properties. Few are downregulated and possess beneficial anti-inflammatory effect. The apolipoprotein M (APOM) is an adipokine whose expression is low during obesity and associated with a metabolically healthy AT. Here, the role of adipose-derived APOM on obesity-associated AT inflammation was investigated by measuring the expression of pro-inflammatory genes in humans and mice models. In 300 individuals with obesity, AT APOM mRNA level was negatively associated to plasma hs-CRP. The inflammatory profile was assessed in Apom-/- and WT mice fed a normal chow diet (NCD), or a high fat diet (HFD) to induce AT inflammation. After HFD, mice had a higher inflammatory profile in AT and liver, and a 50% lower Apom gene expression compared with NCD-fed mice. The Apom deficiency was associated with a higher inflammatory signature in AT compared with WT mice, but not in liver. Adeno-associated viruses encoding human APOM were used to induce APOM overexpression: in vivo, in WT mice AT prior to HFD; in vitro, in human adipocytes which conditioned media was applied to ThP-1 macrophages. The murine AT overexpressing APOM gene had a reduced inflammatory profile. The macrophages treated with APOM-enriched media from adipocytes exhibited lower IL6 and MCP1 gene expression compared with macrophages treated with control media, independently of S1P. Our study highlights a protective role of adipocyte APOM against obesity-induced AT inflammation.

MiR-10a regulates cell death and inflammation in adipose tissue of male mice with diet-induced obesity

ObjectiveAdipose tissue remodeling plays a critical role in obesity-induced metabolic dysfunction, but the underlying molecular mechanisms remain incompletely understood. This study investigates the role of miR-10a-5p in adipose tissue inflammation and metabolic dysfunction induced by a high fat diet (HFD). MethodsMale miR-10a knockout (KO) mice were fed a HFD to induce obesity for up to 16 weeks. RNA sequencing (RNA-seq) analysis was performed to profile mRNA expression and assess the effects of miR-10a-5p KO in gonadal white adipose tissue (gWAT). Additional analyses included immunoblotting, qPCR, histological examination, and validation of the miR-10a-5p target sequence using a dual-luciferase reporter assay. ResultsmiR-10a-5p was highly expressed in gWAT but decreased after 8 weeks of HFD feeding. Over the 16-week HFD period, miR-10a KO mice exhibited greater weight gain and reduced energy expenditure compared to wild-type (WT) controls. gWAT of miR-10a KO mice on a HFD showed an increased population of proinflammatory macrophages, elevated inflammation, and increased cell death, characterized by upregulated apoptosis and necrosis markers. This was also associated with increased triglyceride accumulation in the liver. Mechanistically, the proapoptotic gene Bcl2l11 was identified as a direct target of miR-10a-5p. Loss of miR-10a-5p led to BIM-mediated adipocyte death and inflammation, contributing to mitochondrial metabolic dysregulation, increased fibrosis marker expression, and the onset of inflammation in adipose tissue. ConclusionsThis study demonstrates the significant role of miR-10a-5p and its downstream target BIM in regulating adipocyte death during diet-induced obesity. This signaling pathway presents a potential therapeutic target for modulating obesity-induced inflammation and cell death in adipose tissue.

Alpha-Linolenic Acid Ameliorates Cognitive Impairment and Liver Damage Caused by Obesity.

Obesity is a growing global problem that causes various complications such as diabetes, cognitive dysfunction, cardiovascular diseases, and hepatobiliary disease. Alpha-linolenic acid (ALA) has been reported to exhibit multiple pharmaceutical effects. This study aimed to explore the effects of ALA on obesity-induced adipose tissue accumulation, cognitive impairment, inflammation, and colonic mucosal barrier integrity. Mice were fed with high-fat diet (HFD) and were treated with ALA (60 or 100 mg/kg). Body weight, adipose tissue, serum glucose and lipid levels, glucose resistance, and insulin resistance were measured. Cognitive ability was analyzed using the behavior tests. PTP1B and IRS/p-AKT/p-GSK3β/p-Tau signaling were examined to evaluate inflammation and synaptogenesis. Colon mucosal barrier integrity was examined by Alcian blue staining and expression of the tight junction proteins. The production of pro-inflammatory cytokines and liver damages were evaluated. 3T3-L1 cells were used for in vitro experiments. Cell viability, migration and invasion were detected. The levels of ROS, iron, and ferrous ions were measured to assess ferroptosis. Metabolomic analysis of adipose tissues was performed. ALA treatment prevented HFD-induced adipose tissue accumulation, improved glucose and lipid homeostasis and metabolism. Administration of ALA repressed the HFD-induced increase in insulin levels and insulin resistance index. Serum and colon levels of pro-inflammatory cytokines were decreased after ALA treatment. ALA elevated mitochondrial content in brown adipose tissues. ALA ameliorated obesity-induced cognitive impairment and hippocampal inflammation, enhanced colon mucosa integrity. ALA treatment ameliorated HFD-induced liver damage and lipid accumulation and inhibited differentiation of preadipocyte 3T3-L1 cells into mature adipocytes and induces ferroptosis. Metabolomic analysis suggested that ALA may target the glycerolipid metabolism pathway to ameliorate obesity. Knockdown of AGPAT2 abolished the protective effects of ALA. ALA treatment suppressed adipose accumulation in adipocytes, improved cognitive ability and colon integrity, and alleviated liver damage by modulating the 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2).

Composition of fatty acids in a high-fat diet affects adipose tissue inflammation by inducing calreticulin on adipocytes and activating group 1 innate lymphoid cells.

Obesity-induced adipose tissue inflammation plays a critical role in the development of metabolic diseases. For example, NK1.1+ group 1 innate lymphoid cells (G1-ILCs) in adipose tissues are activated in the early stages of inflammation in response to a high-fat diet (HFD). In this study, we examined whether the composition of fatty acids affected adipose inflammatory responses induced by an HFD. Mice were fed a stearic acid (C18:0)-rich HFD (HFD-S) or a linoleic acid (C18:2)-rich HFD (HFD-L). HFD-L-fed mice showed significant obesity compared with HFD-S-fed mice. Visceral and subcutaneous fat pads were enlarged and contained more NK1.1+KLRG1+ cells, indicating that G1-ILCs were activated in HFD-L-fed mice. We examined early changes in adipose tissues during the first week of HFD intake, and found that mice fed HFD-L showed increased levels of NK1.1+CD11b+KLRG1+ cells in adipose tissues. In adipose tissue culture, addition of 4-hydroxynonenal, the most frequent product of lipid peroxidation derived from unsaturated fatty acids, induced NK1.1+CD11b+CD27- cells. We found that calreticulin, a ligand for the NK activating receptor, was induced on the surface of adipocytes after exposure to 4-hydroxynonenal or a 1-week feeding with HFD-L. Thus, excess fatty acid intake and the activation of G1-ILCs initiate and/or modify adipose inflammation.

Hyaluronic acid-graphene oxide quantum dots nanoconjugate as dual purpose drug delivery and therapeutic agent in meta-inflammation

Type 2 diabetes mellitus (T2DM) predominantly considered a metabolic disease is now being considered an inflammatory disease as well due to the involvement of meta-inflammation. Obesity-induced adipose tissue inflammation (ATI) is one of the earliest phenomena in the case of meta-inflammation, leading to the advent of insulin resistance (IR) and T2DM. The key events of ATI are orchestrated by macrophages, which aggravate the inflammatory state in the tissue upon activation, ultimately leading to systemic chronic low-grade inflammation and Non-Alcoholic Steatohepatitis (NASH) through the involvement of proinflammatory cytokines. The CD44 receptor on macrophages is overexpressed in ATI, NASH, and IR. Therefore, we developed a CD44 targeted Hyaluronic Acid functionalized Graphene Oxide Quantum Dots (GOQD-HA) nanocomposite for tissue-specific delivery of metformin. Metformin-loaded GOQD-HA (GOQD-HA-Met) successfully downregulated the expression of proinflammatory cytokines and restored antioxidant status at lower doses than free metformin in both palmitic acid-induced RAW264.7 cells and diet induced obese mice. Our study revealed that the GOQD-HA nanocarrier enhanced the efficacy of Metformin primarily by acting as a therapeutic agent apart from being a drug delivery platform. The therapeutic properties of GOQD-HA stem from both HA and GOQD having anti-inflammatory and antioxidant properties respectively. This study unravels the function of GOQD-HA as a targeted drug delivery option for metformin in meta-inflammation where the nanocarrier itself acts as a therapeutic agent.Graphical

Allium macrostemon whole extract ameliorates obesity-induced inflammation and endoplasmic reticulum stress in adipose tissue of high-fat diet-fed C57BL/6N mice.

Obesity is a major risk factor for metabolic syndrome and a serious health concern worldwide. Various strategies exist to treat and prevent obesity, including dietary approaches using bioactive ingredients from natural sources. This study aimed to investigate the anti-obesity effect of whole-plant Allium macrostemon (also called as long-stamen chive) extract (AME) as a potential new functional food. C57BL/6N mice were divided into three groups and fed either a control diet (CD), high-fat diet (HFD), or HFD with AME treatment (200 mg/kg BW daily) for 9 weeks. The mice in the CD and HFD groups were treated with vehicle control. AME supplementation reduced HFD-induced body weight gain, fat mass, and adipocyte size. AME suppressed peroxisome proliferator-activated receptor γ and fatty acid synthase mRNA expression, indicating reduced adipogenesis and lipogenesis in adipose tissue. In addition, AME lowered inflammation in adipose tissue, as demonstrated by the lower number of crown-like structures, mRNA, and/or protein expression of macrophage filtration markers, as well as pro-inflammatory cytokines, including F4/80 and IL-6. Endoplasmic reticulum stress was also alleviated by AME administration in adipose tissue. Several phenolic acids known to have anti-obesity effects, including ellagic acid, protocatechuic acid, and catechin, have been identified in AME. By suppressing adipose tissue expansion and inflammation, AME is a potential functional food for the prevention and/or treatment of obesity and its complications.

Apocynin alleviates weight gain and obesity-induced adipose tissue inflammation in high-fat diet-fed C57BL/6 mice.

Obesity involves chronic low-grade inflammation within adipose tissue. Apocynin (APO) is a therapeutic agent for the treatment of inflammatory diseases. Therefore, the present study aimed to investigate whether APO can reduce weight gain and obesity-induced adipose tissue inflammation. C57BL/6 mice were administered APO or orlistat (Orli) as a positive control with a high-fat diet (HFD) for 12 weeks. Lipopolysaccharide-stimulated 3T3-L1 adipocytes were used for the in vitro study. Our results showed a significantly lower white adipose tissue (WAT) mass index in 10 mg/kg APO-treated mice than in 20 mg/kg Orli-treated mice. Moreover, the protein expression of adipose triglyceride lipase, fatty acid synthase, sterol regulatory element-binding transcription factor 1, and peroxisome proliferator-activated receptor γ was reversed in the WAT of 10 mg/kg APO-treated mice. Furthermore, APO reduced the expression of the macrophage marker F4/80, decreased the mRNA levels of tumor necrosis factor-α and monocyte chemoattractant protein-1, and increased the mRNA levels of interleukin-10 in WAT. APO decreased the phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p65 in vivo and in vitro. Notably, APO had a stronger effect on the amelioration of adipose tissue inflammation than Orli did. Our findings lay the foundation for research on the use of APO as an agent to ameliorate weight gain and obesity-induced inflammatory diseases.

Amelioration of obesity-induced white adipose tissue inflammation by Bacillus coagulans T4 in a high-fat diet-induced obese murine model

AimFresh evidence suggests that B. coagulans can be regarded as a promising therapeutic alternative for metabolic disorders. However, the possible effects of this probiotic on obesity-induced adipose tissue inflammation are unknown. MethodsC57BL/6j male mice were assigned to a normal-chow diet (NCD) or a high-fat diet (HFD) for 10 weeks. After this period, HFD-fed mice were randomly divided into two groups; HFD control group and HFD plus B. coagulans T4 (IBRC-N10791) for another 8 weeks. B. coagulans T4 was administrated daily by oral intragastric gavage (1 × 109 colony-forming units). Key findingsHere, we found that B. coagulans successfully mitigated obesity and related metabolic disorder, as indicated by reduced body weight gain, decreased adiposity, and improved glucose tolerance. B. coagulans T4 administration also inhibited HFD-induced macrophage accumulation in white adipose tissue and switched M1 to M2 macrophages. In parallel, B. coagulans T4 treatment attenuated HFD-induced alteration in mRNA expression of pro/anti-inflammatory cytokines and Tlr4 in white adipose tissue. Moreover, B. coagulans T4 supplementation reduced the Firmicutes/Bacteriodetes ratio and increased the number of Lactobacillus and Faecalibacterium compared to the HFD group. Additionally, a significant increase in propionate and acetate levels in the HFD group was seen following B. coagulans T4 administration. SignificanceTaken together, the present study provides evidence that B. coagulans T4 supplementation exerts anti-obesity effects in part through attenuating inflammation in adipose tissue. The present study will have significant implications for obesity management.

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.

Adipose Tissue-Derived CCL5 Enhances Local Pro-Inflammatory Monocytic MDSCs Accumulation and Inflammation via CCR5 Receptor in High-Fat Diet-Fed Mice.

The C-C chemokine motif ligand 5 (CCL5) and its receptors have recently been thought to be substantially involved in the development of obesity-associated adipose tissue inflammation and insulin resistance. However, the respective contributions of tissue-derived and myeloid-derived CCL5 to the etiology of obesity-induced adipose tissue inflammation and insulin resistance, and the involvement of monocytic myeloid-derived suppressor cells (MDSCs), remain unclear. This study used CCL5-knockout mice combined with bone marrow transplantation (BMT) and mice with local injections of shCCL5/shCCR5 or CCL5/CCR5 lentivirus into bilateral epididymal white adipose tissue (eWAT). CCL5 gene deletion significantly ameliorated HFD-induced inflammatory reactions in eWAT and protected against the development of obesity and insulin resistance. In addition, tissue (non-hematopoietic) deletion of CCL5 using the BMT method not only ameliorated adipose tissue inflammation by suppressing pro-inflammatory M-MDSC (CD11b+Ly6G-Ly6Chi) accumulation and skewing local M1 macrophage polarization, but also recruited reparative M-MDSCs (CD11b+Ly6G-Ly6Clow) and M2 macrophages to the eWAT of HFD-induced obese mice, as shown by flow cytometry. Furthermore, modulation of tissue-derived CCL5/CCR5 expression by local injection of shCCL5/shCCR5 or CCL5/CCR5 lentivirus substantially impacted the distribution of pro-inflammatory and reparative M-MDSCs as well as macrophage polarization in bilateral eWAT. These findings suggest that an obesity-induced increase in adipose tissue CCL5-mediated signaling is crucial in the recruitment of tissue M-MDSCs and their trans-differentiation to tissue pro-inflammatory macrophages, resulting in adipose tissue inflammation and insulin resistance.

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.

Lipoxins reduce obesity-induced adipose tissue inflammation in 3D-cultured human adipocytes and explant cultures

SummaryAdipose tissue inflammation drives obesity-related cardiometabolic diseases. Enhancing endogenous resolution mechanisms through administration of lipoxin A4, a specialized pro-resolving lipid mediator, was shown to reduce adipose inflammation and subsequently protects against obesity-induced systemic disease in mice. Here, we demonstrate that lipoxins reduce inflammation in 3D-cultured human adipocytes and adipose tissue explants from obese patients. Approximately 50% of patients responded particularly well to lipoxins by reducing inflammatory cytokines and promoting an anti-inflammatory M2 macrophage phenotype. Responding patients were characterized by elevated systemic levels of C-reactive protein, which causes inflammation in cultured human adipocytes. Responders appeared more prone to producing anti-inflammatory oxylipins and displayed elevated prostaglandin D2 levels, which has been interlinked with transcription of lipoxin-generating enzymes. Using explant cultures, this study provides the first proof-of-concept evidence supporting the therapeutic potential of lipoxins in reducing human adipose tissue inflammation. Our data further indicate that lipoxin treatment may require a tailored personalized-medicine approach.

Nicotinamide Riboside Supplementation Attenuates Obesity-Induced Adipose Tissue Fibrosis and Inflammation in Female Mouse Model

ObjectivesNicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+) precursor. We previously reported that in male diet-induced obesity mice, NR supplementation attenuated liver fibrosis by inhibiting the activation of hepatic stellate cells. However, whether NR elicits a similar effect in females has not been studied. Therefore, in this study, we investigated whether NR consumption can prevent the development of inflammation and fibrosis and improve NAD + metabolism in the liver and white adipose tissue (WAT) in female mice with diet-induced obesity MethodsFemale C57BL/6J mice were fed a high-fat/high-sucrose/high-cholesterol control (HF), or a HF diet supplemented with NR (HF-NR; 400 mg/kg/day) for 20 weeks. The effects of NR on fibrosis and inflammation were assessed by biochemical, molecular, and histological analyses in the liver and gonadal WAT (gWAT). Metabolic rates, energy expenditure, and physical activity of mice were analyzed using indirect calorimetry. ResultsThe body weight of mice fed HF-NR was significantly lower than HF. Also, HF-NR showed reductions in fat mass, glucose intolerance, and serum cholesterol levels compared with HF. In the liver, NAD + content tended toward an increase in the HF-NR, but NR supplementation did not significantly alter liver steatosis and fibrosis, along with no changes in serum alanine aminotransferase levels. In gWAT, the HF-NR group displayed decreased weight and adipocyte size compared with HF. In addition, the numbers of crown-like structures, a marker of inflammation, were markedly reduced in the gWAT of HF-NR compared to the HF. Consistently, NR supplementation decreased the expression of macrophage and proinflammatory M1 macrophage markers. Mice fed HF-NR also exhibited decreased gWAT fibrosis, evidenced by less fibrogenic gene expression and collagen accumulation than HF. Metabolic rates, physical activity, and energy expenditure were significantly higher in the HF-NR group than in HF. ConclusionsNR supplementation increased metabolic rates, energy expenditure, and physical activity, preventing obesity and its-associated inflammation and fibrosis in the WAT of female mice. The data suggest that NR may have sex-dependent effects on tissue-specific inhibition of obesity-induced inflammation and fibrosis. Funding SourcesThis study was supported by NIH 3R01DK108254-04S1.

Obesity, Adipose Tissue, and Inflammation Answered in Questions.

Background. Obesity is a global health problem of epidemic proportions, which is characterized by increased adipose tissue (AT) mass and significant repercussions in different body apparati and systems. AT is a special connective tissue, which contains several types of cells, in addition to adipocytes, and is a highly active endocrine and immune organ, which directly modulates many processes, including energy balance, metabolism, and inflammation. Summary. In this paper, the authors list and attempt to answer in a brief and simple way several questions regarding the complex relationships between obesity, adipose tissue, and inflammation, with the objective to provide an easy way to understand the main changes that occur in this pathological state. The questions are the following: Is adipose tissue only made up of adipocytes? Are adipocytes just a reservoir of free fatty acids? Do different types of fatty tissue exist? If so, which types? Can we further subcategorize the types of adipose tissue? Is it possible to form new adipocytes during adulthood? What is the role of inflammation? What is the role of macrophages? Are macrophages central mediators of obesity-induced adipose tissue inflammation and insulin resistance? What causes macrophage infiltration into adipose tissue? What is the role of hypoxia in AT alterations? Is there cross talk between adipocytes and immune cells? What other changes occur in AT in obesity? Does metabolically healthy obesity really exist? Is this a benign condition? Key messages. Obesity is a complex disease with numerous metabolic consequences, which are mainly the result of dysfunction that occurs in the adipose tissue of patients with this pathology. Understanding the pathophysiology of AT and the changes that occur in obesity would contribute to a better approach to patients with obesity, with the inherent medical implications that could result from this.

Fetuin-A regulates adipose tissue macrophage content and activation in insulin resistant mice through MCP-1 and iNOS: involvement of IFNγ-JAK2-STAT1 pathway.

In the context of obesity-induced adipose tissue (AT) inflammation, migration of macrophages and their polarization from predominantly anti-inflammatory to proinflammatory subtype is considered a pivotal event in the loss of adipose insulin sensitivity. Two major chemoattractants, monocyte chemoattractant protein-1 (MCP-1) and Fetuin-A (FetA), have been reported to stimulate macrophage migration into inflamed AT instigating inflammation. Moreover, FetA could notably modulate macrophage polarization, yet the mechanism(s) is unknown. The present study was undertaken to elucidate the mechanistic pathway involved in the actions of FetA and MCP-1 in obese AT. We found that FetA knockdown in high fat diet (HFD) fed mice could significantly subdue the augmented MCP-1 expression and reduce adipose tissue macrophage (ATM) content thereby indicating that MCP-1 is being regulated by FetA. Additionally, knockdown of FetA in HFD mice impeded the expression of inducible nitric oxide synthase (iNOS) reverting macrophage activation from mostly proinflammatory to anti-inflammatory state. It was observed that the stimulating effect of FetA on MCP-1 and iNOS was mediated through interferon γ (IFNγ) induced activation of JAK2-STAT1-NOX4 pathway. Furthermore, we detected that the enhanced IFNγ expression was accounted by the stimulatory effect of FetA upon the activities of both cJun and JNK. Taken together, our findings revealed that obesity-induced FetA acts as a master upstream regulator of AT inflammation by regulating MCP-1 and iNOS expression through JNK-cJun-IFNγ-JAK2-STAT1 signaling pathway. This study opened a new horizon in understanding the regulation of ATM content and activation in conditions of obesity-induced insulin resistance.

Inflammatory mechanisms linking obesity and tendinopathy.

Chronic tendinopathy is a debilitating tendon disorder with disappointing treatment outcomes. This review focuses on the potential roles of chronic low-grade inflammation in promoting tendinopathy in obesity. A systematic literature search was performed to identify all clinical studies supporting the actions of obesity-associated inflammatory mediators in the development of tendinopathy. The mechanisms of obesity-induced chronic inflammation in adipose tissue are firstly reviewed. Common inflammatory mediators potentially linking obesity and the development of tendinopathy, and their association with mechanical overuse, are discussed, along with pre-clinical evidences and a systematic literature search on clinical studies. The potential contribution of local adipose tissues in the promotion of inflammation, pain and tendon degeneration is then discussed. The future research directions are proposed.Translational potential statementBetter understanding of the roles of obesity-associated inflammatory mediators on tendons will clarify the pathophysiological drivers of tendinopathy in patients with obesity and identify possible treatment targets. Further studies on the mechanisms of obesity-induced chronic inflammation on tendon are a promising direction for the treatment of tendinopathy.

Macrophage polarization state affects lipid composition and the channeling of exogenous fatty acids into endogenous lipid pools

Adipose-tissue-resident macrophages (ATMs) maintain metabolic homeostasis but also contribute to obesity-induced adipose tissue inflammation and metabolic dysfunction. Central to these contrasting effects of ATMs on metabolic homeostasis is the interaction of macrophages with fatty acids. Fatty acid levels are increased within adipose tissue in various pathological and physiological conditions, but appear to initiate inflammatory responses only upon interaction with particular macrophage subsets within obese adipose tissue. The molecular basis underlying these divergent outcomes is likely due to phenotypic differences between ATM subsets, although how macrophage polarization state influences the metabolism of exogenous fatty acids is relatively unknown. Herein, using stable isotope-labeled and nonlabeled fatty acids in combination with mass spectrometry lipidomics, we show marked differences in the utilization of exogenous fatty acids within inflammatory macrophages (M1 macrophages) and macrophages involved in tissue homeostasis (M2 macrophages). Specifically, the accumulation of exogenous fatty acids within triacylglycerols and cholesterol esters is significantly higher in M1 macrophages, while there is an increased enrichment of exogenous fatty acids within glycerophospholipids, ether lipids, and sphingolipids in M2 macrophages. Finally, we show that functionally distinct ATM populations in vivo have distinct lipid compositions. Collectively, this study identifies new aspects of the metabolic reprogramming that occur in distinct macrophage polarization states. The channeling of exogenous fatty acids into particular lipid synthetic pathways may contribute to the sensitivity/resistance of macrophage subsets to the inflammatory effects of increased environmental fatty acid levels.

Role of RAGE in obesity-induced adipose tissue inflammation and insulin resistance

AbatractObesity is known to be associated with adipose tissue inflammation and insulin resistance. Importantly, in obesity, the accumulation of proinflammatory macrophages in adipose tissue correlates with insulin resistance. We hypothesized that the receptor for advanced glycation end products (RAGE) and associated ligands are involved in adipose tissue insulin resistance, and that the activation of the AGE–RAGE axis plays an important role in obesity-associated inflammation. C57BL/6J mice (WT) and RAGE deficient (RAGE−/−) mice were fed a high fat diet (HFD) and subjected to glucose and insulin tolerance tests. Epdidymal adipose tissue (eAT) was collected and adipose stromal vascular cells isolated using flow cytometry. Visceral adipose tissue macrophage polarization was assessed by quantitative real time PCR. Immunoblotting was performed to evaluate the insulin signaling in adipose tissues. In additional studies, cell trafficking was assessed by injecting labeled blood monocytes into recipient mice. RAGE−/− mice displayed improved insulin sensitivity and glucose tolerance, accompanied by decreased body weight and eAT mass. Exogenous methylglyoxal (MGO) impaired insulin-stimulated AKT signaling in adipose tissues from WT mice fed a normal chow diet, but not in RAGE−/− mice. In contrast, in obese mice, treatment with MGO did not reduce insulin-induced phosphorylation of AKT in WT-HFD mice. Moreover, insulin-induced AKT phosphorylation was found to be impaired in adipose tissue from RAGE−/−-HFD mice. RAGE−/− mice displayed improved inflammatory profiles and evidence for increased adipose tissue browning. This observation is consistent with the finding of reduced plasma levels of FFA, glycerol, IL-6, and leptin in RAGE−/− mice compared to WT mice. Collectively the data demonstrate that RAGE-mediated adipose tissue inflammation and insulin-signaling are potentially important mechanisms that contribute to the development of obesity-associated insulin resistance.

Crosstalk between Metabolic Disorders and Immune Cells.

Metabolic syndrome results from multiple risk factors that arise from insulin resistance induced by abnormal fat deposition. Chronic inflammation owing to obesity primarily results from the recruitment of pro-inflammatory M1 macrophages into the adipose tissue stroma, as the adipocytes within become hypertrophied. During obesity-induced inflammation in adipose tissue, pro-inflammatory cytokines are produced by macrophages and recruit further pro-inflammatory immune cells into the adipose tissue to boost the immune response. Here, we provide an overview of the biology of macrophages in adipose tissue and the relationship between other immune cells, such as CD4+ T cells, natural killer cells, and innate lymphoid cells, and obesity and type 2 diabetes. Finally, we discuss the link between the human pathology and immune response and metabolism and further highlight potential therapeutic targets for the treatment of metabolic disorders.

Adipose Tissue Dendritic Cells: Critical Regulators of Obesity-Induced Inflammation and Insulin Resistance.

Chronic inflammation of the adipose tissue (AT) is a critical component of obesity-induced insulin resistance and type 2 diabetes. Adipose tissue immune cells, including AT macrophages (ATMs), AT dendritic cells (ATDCs), and T cells, are dynamically regulated by obesity and participate in obesity-induced inflammation. Among AT resident immune cells, ATDCs are master immune regulators and engage in crosstalk with various immune cells to initiate and regulate immune responses. However, due to confounding markers and lack of animal models, their exact role and contribution to the initiation and maintenance of AT inflammation and insulin resistance have not been clearly elucidated. This paper reviews the current understanding of ATDCs and their role in obesity-induced AT inflammation. We also provide the potential mechanisms by which ATDCs regulate AT inflammation and insulin resistance in obesity. Finally, this review offers perspectives on ways to better dissect the distinct functions and contributions of ATDCs to obesity.