Figure 2 - uploaded by Theresa Ramalho
Content may be subject to copyright.
Metabolic pattern of adipose tissue macrophages (ATMs) in obesity. Studies have reported upregulation of glycolysis which is associated with higher expression of inflammatory cytokines in ATMs.
Source publication
The increased incidence of cancer has been attributed to raised numbers of individuals with obesity/overweight worldwide. Different types of cancers in obese individuals have poor prognosis, high remission rate and resistance to traditional therapies. Literature has identified that lipid metabolism in lipid-laden immune cells, including macrophages...
Contexts in source publication
Context 1
... and of other subpopulations of macrophages residing in other microenvironments ( Figure 2). ...
Context 2
... human monocytes-derived macrophages or murine bone marrow-derived macrophages are stimulated with metabolic substrates (glucose, insulin and palmitate), the expression of metabolic markers is dependent on peroxisome proliferatoractivated receptor (PPAR)-γ [24], a transcription factor which regulates lipid metabolism and promotes anti-inflammatory macrophage responses [25]. Interestingly, TNF-α (tumor necrosis factor alpha) and IL(interleukin)-1β expression is down-regulated by PPARγ [24], suggesting that PPARγ attenuates pro-inflammatory cytokine production during metabolic activation in ATMs of obese subjects (Figure 2). In another study, ATMs of leptin-deficient obese animals (ob/ob) express a transcriptional program of lysosome biogenesis, and lysosome bodies are highly detected in this population. ...
Context 3
... vitro, the differentiation of bone marrow-derived macrophages in the presence of digested adipose tissue increases the expression of Arg1, Il1b, and Nos2, genes involved in lipid uptake (Msr1 and Plin2) and lysosome genes ( Atp6v0d2, Lipa, and Ctsk). In these cells, lipolysis is dependent on the activation of the liposome program, independent of their inflammatory phenotype [26] (Figure 2). In other types of macrophages (Raw264.7, ...
Context 4
... a metabolic dysregulated system, AMPK antagonizes biosynthetic pathways and promotes catabolic processes through regulation of total mitochondrial content mediated by the activation of peroxisome proliferator-activated receptor gamma coactivated 1-(PGC1)α [28]. Mice fed a high fat diet (HFD) that do not express AMPK enhance ATM inflammation and insulin resistance [29] ( Figure 2). In this sense, it is suggested that fatty acid oxidation (FAO) in ATM may protect obesity-associated complications while a fatty acid synthesis program in macrophages worsens obese adipose tissue complications [30]. ...
Context 5
... it was shown that peritoneal macrophages from obese and diabetic mice have an anti-inflammatory phenotype that may explain why obese individuals have an impaired immune response against pathogens, whilst having a predisposition to develop tumors. In this study, peritoneal macrophages display a high expression of liver X receptor (LXR) and sterol regulatory element-binding protein (SREBP) targets, such as Idol, Srebf1, Srebf2, Scd1, and Abca1 (Figure 2). This study did not explore mechanisms for the expression of such metabolic markers, but it was demonstrated that weight loss restores peritoneal macrophage function and thus contributes to the reduction of immune-related comorbidities in patients [33]. ...
Context 6
... metabolism: A different study in mice and humans showed that in obese ATM fatty acid oxidation, glycolysis and glutaminolysis contribute to cytokine release by ATMs, but glycolysis seems to be the most important pathway for inflammatory cytokine production [34] (Figure 2) the expression of anti-inflammatory markers in ATMs [35]. ENOblocktreated mice also have lower LDL/VLDL cholesterol in circulating blood, declined serum level of free fatty acids and less expression of inflammatory markers in stimulated Raw264.7 macrophages [36]. ...
Context 7
... mice also have lower LDL/VLDL cholesterol in circulating blood, declined serum level of free fatty acids and less expression of inflammatory markers in stimulated Raw264.7 macrophages [36]. Classically, active HIF-1α promotes glycolysis by inducing the expression of enzymes in the glycolysis pathway ( Figure 2). However, HIF-1α appears to play no critical role in pro-inflammatory activation of ATMs during early stages of obesity [37]. ...
Similar publications
Macrophages are key components of innate immunity, and they play critical roles in heart health and diseases. Following acute myocardial infarction (MI), infiltrating macrophages undergo drastic phenotypic transition from pro-inflammatory in the early stage to pro-healing in the late stage. Transcriptome analyses of macrophage in the infarct zone s...
Citations
... 2,13 Moreover, non-infectious pathologic conditions can alter the tissue microenvironment and impact TMFs metabolism and function. 1,2,14 For instance, hypertrophy of WAT upon overnutrition causes excess lipid-load and adipocyte death in obese individuals. This results in the adoption of an inflammatory state by a population of obese WAT-MFs that subsequently contribute to the development of metabolic syndrome, insulin resistance, and lipid accumulation in the liver. ...
... This is likely due to a lower lipid burden of those anti-inflammatory compared with pro-inflammatory CD11c + and/or CD9 + eWAT-MFs, as the latter predominate in CLS. 14,19,51 Of note, the numbers and phenotype of circulating monocytes, which can give rise to eWAT-MFs in obesity, were unaffected in Lyz2DTfam mice ( Figure S7G). In accordance with decreased pro-inflammatory eWAT-MF presence, obese ll Article and S7H). ...
... Those obese eWAT-MFs in CLS express CD11c and CD9, accumulate lipids and become pro-inflammatory. 2,14,19,51 Interference with increases in intracellular ROS can impair pro-inflammatory macrophage activation. 60 Although we observed elevated ROS amounts at baseline in Tfam-deficient TMFs, we cannot entirely exclude a potential contribution of alterations of ROS amounts to the reduction of pro-inflammatory Lyz2DTfam eWAT-MFs. ...
In vitro studies have associated oxidative phosphorylation (OXPHOS) with anti-inflammatory macrophages, whereas pro-inflammatory macrophages rely on glycolysis. However, the metabolic needs of macrophages in tissues (TMFs) to fulfill their homeostatic activities are incompletely understood. Here, we identified OXPHOS as the highest discriminating process among TMFs from different organs in homeostasis by analysis of RNA-seq data in both humans and mice. Impairing OXPHOS in TMFs via Tfam deletion differentially affected TMF populations. Tfam deletion resulted in reduction of alveolar macrophages (AMs) due to impaired lipid-handling capacity, leading to increased cholesterol content and cellular stress, causing cell-cycle arrest in vivo. In obesity, Tfam depletion selectively ablated pro-inflammatory lipid-handling white adipose tissue macrophages (WAT-MFs), thus preventing insulin resistance and hepatosteatosis. Hence, OXPHOS, rather than glycolysis, distinguishes TMF populations and is critical for the maintenance of TMFs with a high lipid-handling activity, including pro-inflammatory WAT-MFs. This could provide a selective therapeutic targeting tool.
... This increases the uptake and metabolism of glucose via the glycolytic pathway. Moreover, the little oxidation of succinate by succinate dehydrogenase in macrophages stimulated by LPS induces the generation of mitochondrial reactive oxygen species (mtROS) [18,19]. These byproducts are recruited into phagosomes for bacterial killing. ...
... These byproducts are recruited into phagosomes for bacterial killing. In addition, the ROS cause oxidative damage to the DNA, and as a result, the poly (ADP-ribose) polymerase (PARP) enzymes are activated [19]. These enzymes consume a lot of NAD leaving the M1 macrophages to rely on salvage pathways for NAD + . ...
Macrophages are phagocytic cells that reside within body tissues. They can either be derived from circulating monocytes or can arise during the embryonic stage of fetal development. Tissue macrophages are predominantly of embryonic origin. But can result from differentiation of circulating monocytes to become resident macrophages either in pathological or physiological state. Macrophages are classified based on their tissue location and method of activation. Classically activated macrophages are the M1 phenotype while alternatively activated macrophages are M2 phenotype. M1 macrophages are pro-inflammatory since they secrete cytokines that attract inflammatory mediators. They are majorly activated by either interferon-gamma or lipopolysaccharide molecules. M2 macrophages are anti-inflammatory and mediate tissue healing and repair. They are activated by cytokines such as interleukin four, ten, and thirteen. The metabolic profiles of these classes of macrophages are intrinsically different and complex yet intertwined. M1 macrophages depend on aerobic glycolysis for energy production while M2 macrophages rely on aerobic fatty acid oxidation pathways. These metabolic pathways optimize macrophage functioning. Regulation of both activation and metabolism depends on transcriptional factors such as STAT 1 and 6, and IRF. Defects in these pathways lead to development of disorders related to macrophage activation and metabolism.
... Nutritional challenges, such as refeeding after starvation or excess calorie intake, systemically affect the activities and metabolism of macrophages in tissues, including white adipose tissue (WAT), pancreas, liver, peritoneum and brain. Prolonged diet-driven perturbations of tissue macrophages are associated with pathologies such as type II diabetes, nonalcoholic fatty liver disease (NAFLD) and cancer [99,[175][176][177][178][179]. During obesity, persistent overnutrition causes lipid accumulation and hypertrophy of WAT. ...
... In conjunction, this activates adipose tissue macrophages (ATMs) to secrete proinflammatory mediators such as tumor necrosis factor (TNF)α or IL-1β that, in turn, stimulate inflammatory pathways such as the c-Jun N-terminal kinase (JNK) or inhibitor of nuclear factor kappa-B kinase subunit (IKK)β pathways in adipocytes. These mechanisms interfere with insulin signaling, culminating in insulin resistance, lipid accumulation in the liver or NAFLD and metabolic syndrome [175][176][177]. Liverresident macrophages, such as KCs or monocyte-derived macrophages, react to systemic inflammation, gut-derived metabolites and other factors during NAFLD and can foster its progression to nonalcoholic steatohepatitis (NASH), fibrosis and liver cirrhosis. ...
... The unique metabolic activation of ATMs during diet-induced obesity can largely be ascribed to characteristics of the dramatically expanded WAT microenvironment, the creation of hypoxia due to inadequate angiogenesis, the release of danger signals by dying adipocytes and the abundance of (adipocytederived) lipids and fatty acids [175,176,193]. However, changes in the bioenergetics of ATMs may also be influenced by the almost exclusive monocytic origin of ATMs in obese mice [189,193,194]. ...
Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components. The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells. Macrophages are embryo- or adult bone marrow-derived leukocytes that are key for healthy tissue homeostasis but can also contribute to pathologies such as metabolic syndrome, atherosclerosis, fibrosis or cancer. Macrophage metabolism has largely been studied in vitro. However, different organs contain diverse macrophage populations that specialize in distinct and often tissue-specific functions. This context specificity creates diverging metabolic challenges for tissue macrophage populations to fulfill their homeostatic roles in their particular microenvironment and conditions their response in pathological conditions. Here, we outline current knowledge on the metabolic requirements and adaptations of macrophages located in tissues during homeostasis and selected diseases.
... There are several subtypes of macrophages in the hypertrophic fat. TREM2+ macrophage is a subtype that downregulates adipocyte growth [24]. Interestingly, Trem2 expression was downregulated by EPA in our data. ...
This study aims to investigate the global profiling of genes and miRNAs expression to explore the regulatory effects of eicosapentaenoic acid (EPA) in visceral adipose tissue (VAT) of obese mice. We used male mice, fed either a high-fat diet (HF) or HF supplemented with EPA (HF-EPA), for 11 weeks. RNA, and small RNA profiling, were performed by RNAseq analysis. We conducted analyses using Ingenuity Pathway Analysis software (IPA ®) and validated candidate genes and miRNAs related to lipid mediators and inflammatory pathways using qRT-PCR. We identified 153 genes differentially downregulated, and 62 microRNAs differentially expressed in VAT from HF-EPA compared to HF. Genes with a positive association with inflammation, chemotaxis, insulin resistance, and inflammatory cell death, such as Irf5, Alox5ap, Tlrs, Cd84, Ccr5, Ccl9, and Casp1, were downregulated by EPA. Moreover, EPA significantly reduced LTB4 levels, a lipid mediator with a central role in inflammation and insulin resistance in obesity. The pathways and mRNA/microRNA interactions identified in our study corroborated with data validated for inflammatory genes and miRNAs. Together, our results identified key VAT inflammatory targets and pathways, which are regulated by EPA. These targets merit further investigation to better understand the protective mechanisms of EPA in obesity-associated inflammation.
Objective
Pro-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.
Methods
Here 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.
Results
KO 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.
Conclusions
Collectively, 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.
Hyperactivation of the immune system through obesity and diabetes may enhance infection severity complicated by Acute Respiratory Distress Syndrome (ARDS). The objective was to determine the circulatory biomarkers for macrophage activation at baseline and after serum glucose normalization in obese type 2 diabetes (OT2D) subjects. A case-controlled interventional pilot study in OT2D (n = 23) and control subjects (n = 23). OT2D subjects underwent hyperinsulinemic clamp to normalize serum glucose. Plasma macrophage-related proteins were determined using Slow Off-rate Modified Aptamer-scan plasma protein measurement at baseline (control and OT2D subjects) and after 1-h of insulin clamp (OT2D subjects only). Basal M1 macrophage activation was characterized by elevated levels of M1 macrophage-specific surface proteins, CD80 and CD38, and cytokines or chemokines (CXCL1, CXCL5, RANTES) released by activated M1 macrophages. Two potent M1 macrophage activation markers, CXCL9 and CXCL10, were decreased in OT2D. Activated M2 macrophages were characterized by elevated levels of plasma CD163, TFGβ-1, MMP7 and MMP9 in OT2D. Conventional mediators of both M1 and M2 macrophage activation markers (IFN-γ, IL-4, IL-13) were not altered. No changes were observed in plasma levels of M1/M2 macrophage activation markers in OT2D in response to acute normalization of glycemia. In the basal state, macrophage activation markers are elevated, and these reflect the expression of circulatory cytokines, chemokines, growth factors and matrix metalloproteinases in obese individuals with type 2 diabetes, that were not changed by glucose normalisation. These differences could potentially predispose diabetic individuals to increased infection severity complicated by ARDS.
Clinical trial reg. no: NCT03102801; registration date April 6, 2017.
