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Background: Exercise is recognized for its broad health benefits, influencing various physiological processes, including the behavior of adipose tissue macrophages (ATMs). While existing studies mainly associate ATM activity with obesity and metabolic syndrome, our study explores the impact of aerobic exercise on ATM microRNA expression profiling in a non-obese context, highlighting its general health-promoting mechanisms. Methods: Sixty male C57BL/6 mice were randomly assigned to either a sedentary (S) or an exercise (E) group. The S group remained inactive, while the E group underwent a one-week treadmill adaptation, followed by an 8-week aerobic treadmill exercise protocol (60 min/day, 5 days/week, at 65%-75% VO2max). Posttraining, glucose tolerance and the serum lipid levels were measured in mice subjected to both exercise and non-exercise conditions. ATMs harvested from visceral adipose tissues were analyzed and sorted using flow cytometer. To further investigate the effects of exercise in ATMs at the molecular level, miRNA microarray analysis was performed, followed by bioinformatic analysis. Results: The 8-week regimen of moderate-intensity aerobic exercise ameliorated glucolipid metabolism and fostered a dynamic shift toward an M2 macrophage phenotype in the adipose tissue, independent of obesity. A total of 62 differentially expressed miRNAs were identified in ATMs of mice postexercise. Notably, six miRNAs (miR-212-5p, miR-511-5p, miR-7b-5p, miR-142- 3p, miR-1894-3p, and miR-31-5p) as well as their target gene were consistently altered and associated with macrophage polarization and metabolic regulation. Conclusion: Our findings broaden the understanding of how exercise regulates ATM functions through significant changes in microRNA profiles, emphasizing its potential to enhance health and prevent chronic conditions. This study supports the application of aerobic exercise for its preventive effects on chronic diseases and underscores the importance of microRNA profiling in understanding the immune-modulatory impacts of exercise. [ABSTRACT FROM AUTHOR]

The importance of macrophages in adipose tissue (AT) homeostasis and inflammation is well established. However, the potential cues that regulate their function remain incompletely understood. To bridge this important gap, we sought to characterize novel pathways involved using a mouse model of diet‐induced obesity. By performing transcriptomics analysis of AT macrophages (ATMs), we found that late‐stage ATMs from high‐fat diet mice presented with perturbed Notch signaling accompanied by robust proinflammatory and metabolic changes. To explore the hypothesis that the deregulated Notch pathway contributes to the development of AT inflammation and diet‐induced obesity, we employed a genetic approach to abrogate myeloid Notch1 and Notch2 receptors. Our results revealed that the combined loss of Notch1 and Notch2 worsened obesity‐related metabolic dysregulation. Body and AT weight gain was higher, blood glucose levels increased and metabolic parameters were substantially worsened in deficient mice fed high‐fat diet. Moreover, serum insulin and leptin were elevated as were triglycerides. Molecular analysis of ATMs showed that deletion of Notch receptors escalated inflammation through the induction of an M1‐like pro‐inflammatory phenotype. Our findings thus support a protective role of myeloid Notch signaling in adipose tissue inflammation and metabolic dysregulation. [ABSTRACT FROM AUTHOR]

Macrophages, a heterogeneous population of innate immune cells, exhibit remarkable plasticity and play pivotal roles in coordinating immune responses and maintaining tissue homeostasis within the context of metabolic diseases. The activation of inflammatory macrophages in obese adipose tissue leads to detrimental effects, inducing insulin resistance through increased inflammation, impaired thermogenesis, and adipose tissue fibrosis. Meanwhile, adipose tissue macrophages also play a beneficial role in maintaining adipose tissue homeostasis by regulating angiogenesis, facilitating the clearance of dead adipocytes, and promoting mitochondrial transfer. Exploring the heterogeneity of macrophages in obese adipose tissue is crucial for unraveling the pathogenesis of obesity and holds significant potential for targeted therapeutic interventions. Recently, the dual effects and some potential regulatory mechanisms of macrophages in adipose tissue have been elucidated using single-cell technology. In this review, we present a comprehensive overview of the intricate activation mechanisms and diverse functions of macrophages in adipose tissue during obesity, as well as explore the potential of drug delivery systems targeting macrophages, aiming to enhance the understanding of current regulatory mechanisms that may be potentially targeted for treating obesity or metabolic diseases. [ABSTRACT FROM AUTHOR]

As a result of an unhealthy diet and limited physical activity, obesity has become a widespread pandemic worldwide and is an important predictor for the development of cardiovascular disease. Obesity is often characterized by a pro-inflammatory environment in white adipose tissue (WAT), mainly due to increased macrophage infiltration. These immune cells boost their lipid concentrations by accumulating the content of dying adipocytes. As the lysosome is highly involved in lipid handling, the progressive lipid accumulation may result in lysosomal stress and a metabolic shift. Recent studies have identified glycoprotein non-metastatic melanoma protein B (GPNMB) as a novel marker of inflammatory diseases. GPNMB is a type I transmembrane protein on the cell surface of various cell types, such as macrophages, dendritic cells, osteoblasts, and microglia, from which it can be proteolytically cleaved into a soluble molecule. It is induced by lysosomal stress via microphthalmia-associated transcription factor and thus has been found to be upregulated in many lysosomal storage disorders. In addition, a clear connection between GPNMB and obesity was recently established. GPNMB was shown to have protective and anti-inflammatory effects in most cases, preventing the progression of obesity-related metabolic disorders. In contrast, soluble GPNMB likely has the opposite effect and promotes lipogenesis in WAT. This review aims to summarize and clarify the role of GPNMB in the progression of obesity and to highlight its potential use as a biomarker for lipid-associated disorders. [ABSTRACT FROM AUTHOR]

Background and Aims: Obesity may be a risk factor for severe acute pancreatitis (SAP). However, its precise mechanism is not yet fully understood. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Abstract Obesity is one of the most serious global health problems, with an incidence that increases yearly and coincides with the development of cancer. Adipose tissue macrophages (ATMs) are particularly important in this context and contribute to linking obesity-related inflammation and tumor progression. However, the functions of ATMs on the progression of obesity-associated cancer remain unclear. In this review, we describe the origins, phenotypes, and functions of ATMs. Subsequently, we summarize the potential mechanisms on the reprogramming of ATMs in the obesity-associated microenvironment, including the direct exchange of dysfunctional metabolites, inordinate cytokines and other signaling mediators, transfer of extracellular vesicle cargo, and variations in the gut microbiota and its metabolites. A better understanding of the properties and functions of ATMs under conditions of obesity will lead to the development of new therapeutic interventions for obesity-related cancer.

Adipose tissue macrophages (ATM) are an essential type of immune cells in adipose tissue. Obesity induces the inflammation of adipose tissues, as expressed by ATM accumulation, that is more likely to become a source of systemic metabolic diseases, including insulin resistance. The process is characterized by the transcriptional regulation of inflammatory pathways by virtue of signaling molecules such as cytokines and free fatty acids. Notably, posttranslational modification (PTM) is a key link for these signaling molecules to trigger the proinflammatory or anti-inflammatory phenotype of ATMs. This review focuses on summarizing the functions and molecular mechanisms of ATMs regulating inflammation in obese adipose tissue. Furthermore, the role of PTM is elaborated, hoping to identify new horizons of treatment and prevention for obesity-mediated metabolic disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Obesity is a chronic, relapsing, and multifactorial disease characterized by excessive accumulation of adipose tissue (AT), and is associated with inflammation mainly in white adipose tissue (WAT) and an increase in pro-inflammatory M1 macrophages and other immune cells. This milieu favors the secretion of cytokines and adipokines, contributing to AT dysfunction (ATD) and metabolic dysregulation. Numerous articles link specific changes in the gut microbiota (GM) to the development of obesity and its associated disorders, highlighting the role of diet, particularly fatty acid composition, in modulating the taxonomic profile. The aim of this study was to analyze the effect of a medium-fat-content diet (11%) supplemented with omega-3 fatty acids (D2) on the development of obesity, and on the composition of the GM compared with a control diet with a low fat content (4%) (D1) over a 6-month period. The effect of omega-3 supplementation on metabolic parameters and the modulation of the immunological microenvironment in visceral adipose tissue (VAT) was also evaluated. Six-weeks-old mice were adapted for two weeks and then divided into two groups of eight mice each: a control group D1 and the experimental group D2. Their body weight was recorded at 0, 4, 12, and 24 weeks post-differential feeding and stool samples were simultaneously collected to determine the GM composition. Four mice per group were sacrificed on week 24 and their VAT was taken to determine the immune cells phenotypes (M1 or M2 macrophages) and inflammatory biomarkers. Blood samples were used to determine the glucose, total LDL and HDL cholesterol LDL, HDL and total cholesterol, triglycerides, liver enzymes, leptin, and adiponectin. Body weight measurement showed significant differences at 4 (D1 = 32.0 ± 2.0 g vs. D2 = 36.2 ± 4.5 g, p-value = 0.0339), 12 (D1 = 35.7 ± 4.1 g vs. D2 = 45.3 ± 4.9 g, p-value = 0.0009), and 24 weeks (D1 = 37.5 ± 4.7 g vs. D2 = 47.9 ± 4.7, p-value = 0.0009). The effects of diet on the GM composition changed over time: in the first 12 weeks, α and β diversity differed considerably according to diet and weight increase. In contrast, at 24 weeks, the composition, although still different between groups D1 and D2, showed changes compared with previous samples, suggesting the beneficial effects of omega-3 fatty acids in D2. With regard to metabolic analysis, the results did not reveal relevant changes in biomarkers in accordance with AT studies showing an anti-inflammatory environment and conserved structure and function, which is in contrast to reported findings for pathogenic obesity. In conclusion, the results suggest that the constant and sustained administration of omega-3 fatty acids induced specific changes in GM composition, mainly with increases in Lactobacillus and Ligilactobacillus species, which, in turn, modulated the immune metabolic response of AT in this mouse model of obesity. [ABSTRACT FROM AUTHOR]

Abstract Background Adipose tissue inflammation is considered as one of the major mechanisms underlying the pathogenesis of insulin resistance and complications in diabetes. Here, we aimed to study the effects of adipose-derived stromal cells on diabetes-induced insulin resistance and M1 cytokine expression. Methods Stromal vascular fractions (SVFs) purified from the inguinal adipose tissue of diabetic mice were treated with plasma from either nondiabetic (Lepr +/+) or diabetic (Lepr db/db ) mice and injected into the inguinal white adipose tissue of Lepr db/db mice. Results We found that diabetic plasma treatment induced, whereas nondiabetic plasma suppressed TNF-α, IL-1β, and dipeptidyl peptidase 4 (DPP4) mRNA expression in SVFs in vitro. Importantly, the injection of nondiabetic plasma-treated SVFs significantly decreased TNF-α, IL-6, IL-1β, CCL2, and IL-33 and induced IL-10 mRNA expression in adipose tissue of Lepr db/db mice in vivo. Furthermore, we observed that nondiabetic plasma-treated SVFs increased mRNA expression of Foxp3 in adipose tissue macrophages and Foxp3 in adipose CD4+ T cells, decreased CD11b+CD11c+ cells in adipose tissue, and suppressed mRNA expression of ICAM-1, FCM3, IL-6, IL-1β, iNOS, TNF-α, and DPP4 as well as protein expression of DPP4 and phosphorylated JNK and NF-κB in the liver of Lepr db/db mice. Moreover, we found that nondiabetic plasma-treated SVFs increased Akt activation following insulin administration and attenuated glucose intolerance in Lepr db/db mice. Conclusions Our results demonstrate that nondiabetic plasma inhibits M1 but increases M2 cytokine expression in adipose tissue of diabetic mice. Most importantly, our findings reveal that nondiabetic plasma-treated SVFs are capable of mitigating diabetes-induced plasma DPP4 activity, liver inflammation, and insulin resistance and that may be mediated through suppressing M1 cytokines but increasing IL-10 and Tregs in adipose tissue. Altogether, our findings suggest that adipose stromal cell-based therapy could potentially be developed as an efficient therapeutic strategy for the treatment of diabetes.

Introduction: Weight loss improves obesity-associated diabetes risk. However, most individuals regain weight, which worsens the risk of developing diabetes and cardiovascular disease. We previously reported that male mice retain obesity-associated immunological changes even after weight loss, suggesting that immune cells may remember the state of obesity. Therefore, we hypothesized that cycles of weight gain and loss, otherwise known as weight cycling, can induce innate memory in adipose macrophages. Methods: Bone marrow derived macrophages were primed with palmitic acid or adipose tissue conditioned media in a culture model of innate immune memory. Mice also put on low fat or high fat diets over 14-27 weeks to induce weight gain, weight loss, and weight cycling. Results: Priming cells with palmitic acid or adipose tissue conditioned media from obese mice increased maximal glycolysis and oxidative phosphorylation and increased LPS-induced TNFα and IL-6 production. Palmitic acid effects were dependent on TLR4 and impaired by methyltransferase inhibition and AMPK activation. While weight loss improved glucose tolerance in mice, adipose macrophages were primed for greater activation to subsequent stimulation by LPS ex vivo as measured by cytokine production. In the model of weight cycling, adiposemacrophages had elevatedmetabolism and secreted higher levels of basal TNFα, suggesting that weight loss can also prime macrophages for heighted activation to weight regain. Discussion: Together, these data suggest that weight loss following obesity can prime adipose macrophages for enhanced inflammation upon weight regain. This innate immune memory response may contribute to worsened glucose tolerance following weight cycling. [ABSTRACT FROM AUTHOR]

Obesity is one of the most serious global health problems, with an incidence that increases yearly and coincides with the development of cancer. Adipose tissue macrophages (ATMs) are particularly important in this context and contribute to linking obesity-related inflammation and tumor progression. However, the functions of ATMs on the progression of obesity-associated cancer remain unclear. In this review, we describe the origins, phenotypes, and functions of ATMs. Subsequently, we summarize the potential mechanisms on the reprogramming of ATMs in the obesity-associated microenvironment, including the direct exchange of dysfunctional metabolites, inordinate cytokines and other signaling mediators, transfer of extracellular vesicle cargo, and variations in the gut microbiota and its metabolites. A better understanding of the properties and functions of ATMs under conditions of obesity will lead to the development of new therapeutic interventions for obesity-related cancer. [ABSTRACT FROM AUTHOR]

Increasing adipogenesis has been explored to treat metabolic diseases and atherosclerosis through the release of adiponectin. The effects and mechanism of platelet-rich plasma treatment on fat graft survival and adipogenesis have not been clarified. Here, we aimed to study the effects of monocyte chemoattractant protein-1 (MCP-1)-supplemented plasma on adipogenesis-related gene expression and adiponectin levels. Stromal vascular fractions (SVFs) purified from the inguinal adipose tissue of obese and diabetic (Leprdb/db) mice were treated with plasma from control (Lepr+/+) mice supplemented with 10 or 50 ng of MCP-1. The expression of adiponectin and interleukin-33 (IL-33) mRNA in adipose tissue was increased in Leprdb/db mice, whereas control (Lepr+/+) plasma reduced expression of IL-33 mRNA as well as peroxisome proliferator-activated receptor gamma (PPARγ), pJNK, and pNF-κB protein, and increased the expression of IL-10 mRNA in SVFs of Leprdb/db mice. MCP-1-supplemented control plasma increased the expression of adiponectin, CCAAT-enhancer-binding protein α (C/EBPα), dipeptidyl peptidase 4 (DPP4), IL-33, and PDGFα mRNA and the expression of adiponectin protein as well as PPARγ of SVFs and the expression of PPARγ mRNA in adipose tissue macrophages (ATMs). Injection of MCP-1-supplemented plasma into adipose tissue of Leprdb/db mice increased the expression of IL-33 and Col3a1 mRNA in SVFs and IL-33, FABP4, PDGFα, PPARγ and PPARγ2 of ATMs, protein expression of adiponectin and PPARγ of SVFs, and plasma adiponectin levels, as well as DPP4 activity. In conclusion, our results demonstrate that control plasma decreases adipogenesis and increases IL-10, and decreases IL-33, pJNK, and pNF-κB in adipose tissue. MCP-1-supplemented plasma enhances adipogenesis-related gene expression in SVFs and adiponectin levels, which may be mediated through an increase of IL-33 and PPARγ. Thus, our findings suggest that MCP-1-supplemented plasma represents a novel therapy to stimulate local adipogenesis and systemic adiponectin levels. [ABSTRACT FROM AUTHOR]

Obesity usually is accompanied by inflammation of fat tissue, with a prominent role of visceral fat. Chronic inflammation in obese fat tissue is of a lower grade than acute immune activation for clearing the tissue from an infectious agent. It is the loss of adipocyte metabolic homeostasis that causes activation of resident immune cells for supporting tissue functions and regaining homeostasis. Initially, the excess influx of lipids and glucose in the context of overnutrition is met by adipocyte growth and proliferation. Eventual lipid overload of hypertrophic adipocytes leads to endoplasmic reticulum stress and the secretion of a variety of signals causing increased sympathetic tone, lipolysis by adipocytes, lipid uptake by macrophages, matrix remodeling, angiogenesis, and immune cell activation. Pro-inflammatory signaling of adipocytes causes the resident immune system to release increased amounts of pro-inflammatory and other mediators resulting in enhanced tissue-protective responses. With chronic overnutrition, these protective actions are insufficient, and death of adipocytes as well as senescence of several tissue cell types is seen. This structural damage causes the expression or release of immunostimulatory cell components resulting in influx and activation of monocytes and many other immune cell types, with a contribution of stromal cells. Matrix remodeling and angiogenesis is further intensified as well as possibly detrimental fibrosis. The accumulation of senescent cells also may be detrimental via eventual spread of senescence state from affected to neighboring cells by the release of microRNA-containing vesicles. Obese visceral fat inflammation can be viewed as an initially protective response in order to cope with excess ambient nutrients and restore tissue homeostasis but may contribute to tissue damage at a later stage. [ABSTRACT FROM AUTHOR]

IntroductionWeight loss improves obesity-associated diabetes risk. However, most individuals regain weight, which worsens the risk of developing diabetes and cardiovascular disease. We previously reported that male mice retain obesity-associated immunological changes even after weight loss, suggesting that immune cells may remember the state of obesity. Therefore, we hypothesized that cycles of weight gain and loss, otherwise known as weight cycling, can induce innate memory in adipose macrophages.MethodsBone marrow derived macrophages were primed with palmitic acid or adipose tissue conditioned media in a culture model of innate immune memory. Mice also put on low fat or high fat diets over 14-27 weeks to induce weight gain, weight loss, and weight cycling. ResultsPriming cells with palmitic acid or adipose tissue conditioned media from obese mice increased maximal glycolysis and oxidative phosphorylation and increased LPS-induced TNFα and IL-6 production. Palmitic acid effects were dependent on TLR4 and impaired by methyltransferase inhibition and AMPK activation. While weight loss improved glucose tolerance in mice, adipose macrophages were primed for greater activation to subsequent stimulation by LPS ex vivo as measured by cytokine production. In the model of weight cycling, adipose macrophages had elevated metabolism and secreted higher levels of basal TNFα, suggesting that weight loss can also prime macrophages for heighted activation to weight regain.DiscussionTogether, these data suggest that weight loss following obesity can prime adipose macrophages for enhanced inflammation upon weight regain. This innate immune memory response may contribute to worsened glucose tolerance following weight cycling.

Obesity-induced metabolic syndrome is a rapidly growing conundrum, reaching epidemic proportions globally. Chronic inflammation in obese adipose tissue plays a key role in metabolic syndrome with a series of local and systemic effects such as inflammatory cell infiltration and inflammatory cytokine secretion. Adipose tissue macrophages (ATM), as one of the main regulators in this process, are particularly crucial for pharmacological studies on obesity-related metabolic syndrome. Ponatinib, a multi-targeted tyrosine kinase inhibitor originally used to treat leukemia, has recently been found to improve dyslipidemia and atherosclerosis, suggesting that it may have profound effect on metabolic syndrome, although the mechanisms underlying have not yet been revealed. Here we discovered that ponatinib significantly improved insulin sensitivity in leptin deficient obese mice. In addition to that, ponatinib treatment remarkably ameliorated high fat diet-induced hyperlipidemia and inhibited ectopic lipid deposition in the liver. Interestingly, although ponatinib did not reduce but increase the weight of white adipose tissue (WAT), it remarkably suppressed the inflammatory response in WAT and preserved its function. Mechanistically, we showed that ponatinib had no direct effect on hepatocyte or adipocyte but attenuated free fatty acid (FFA) induced macrophage transformation from pro-inflammatory to anti-inflammatory phenotype. Moreover, adipocytes co-cultured with FFA-treated macrophages exhibited insulin resistance, while pre-treat these macrophages with ponatinib can ameliorate this process. These results suggested that the beneficial effects of ponatinib on metabolic disorders are achieved by inhibiting the inflammatory phenotypic transformation of ATMs, thereby maintaining the physiological function of adipose tissue under excessive obesity. The data here not only revealed the novel therapeutic function of ponatinib, but also provided a theoretical basis for the application of multi-target tyrosine kinase inhibitors in metabolic diseases.

Background: Adipose tissue inflammation is considered as one of the major mechanisms underlying the pathogenesis of insulin resistance and complications in diabetes. Here, we aimed to study the effects of adipose-derived stromal cells on diabetes-induced insulin resistance and M1 cytokine expression. Methods: Stromal vascular fractions (SVFs) purified from the inguinal adipose tissue of diabetic mice were treated with plasma from either nondiabetic (Lepr+/+) or diabetic (Leprdb/db) mice and injected into the inguinal white adipose tissue of Leprdb/db mice. Results: We found that diabetic plasma treatment induced, whereas nondiabetic plasma suppressed TNF-α, IL-1β, and dipeptidyl peptidase 4 (DPP4) mRNA expression in SVFs in vitro. Importantly, the injection of nondiabetic plasma-treated SVFs significantly decreased TNF-α, IL-6, IL-1β, CCL2, and IL-33 and induced IL-10 mRNA expression in adipose tissue of Leprdb/db mice in vivo. Furthermore, we observed that nondiabetic plasma-treated SVFs increased mRNA expression of Foxp3 in adipose tissue macrophages and Foxp3 in adipose CD4+ T cells, decreased CD11b+CD11c+ cells in adipose tissue, and suppressed mRNA expression of ICAM-1, FCM3, IL-6, IL-1β, iNOS, TNF-α, and DPP4 as well as protein expression of DPP4 and phosphorylated JNK and NF-κB in the liver of Leprdb/db mice. Moreover, we found that nondiabetic plasma-treated SVFs increased Akt activation following insulin administration and attenuated glucose intolerance in Leprdb/db mice. Conclusions: Our results demonstrate that nondiabetic plasma inhibits M1 but increases M2 cytokine expression in adipose tissue of diabetic mice. Most importantly, our findings reveal that nondiabetic plasma-treated SVFs are capable of mitigating diabetes-induced plasma DPP4 activity, liver inflammation, and insulin resistance and that may be mediated through suppressing M1 cytokines but increasing IL-10 and Tregs in adipose tissue. Altogether, our findings suggest that adipose stromal cell-based therapy could potentially be developed as an efficient therapeutic strategy for the treatment of diabetes. [ABSTRACT FROM AUTHOR]

Obesity and associated diseases, such as diabetes, have reached epidemic proportions globally. In this era of "diabesity", white adipose tissue (WAT) has become a target of high interest for therapeutic strategies. To gain insights into mechanisms of adipose (patho‐)physiology, researchers traditionally relied on animal models. Leveraging Organ‐on‐Chip technology, a microphysiological in vitro model of human WAT is introduced: a tailored microfluidic platform featuring vasculature‐like perfusion that integrates 3D tissues comprising all major WAT‐associated cellular components (mature adipocytes, organotypic endothelial barriers, stromovascular cells including adipose tissue macrophages) in an autologous manner and recapitulates pivotal WAT functions, such as energy storage and mobilization as well as endocrine and immunomodulatory activities. A precisely controllable bottom‐up approach enables the generation of a multitude of replicates per donor circumventing inter‐donor variability issues and paving the way for personalized medicine. Moreover, it allows to adjust the model's degree of complexity via a flexible mix‐and‐match approach. This WAT‐on‐Chip system constitutes the first human‐based, autologous, and immunocompetent in vitro adipose tissue model that recapitulates almost full tissue heterogeneity and can become a powerful tool for human‐relevant research in the field of metabolism and its associated diseases as well as for compound testing and personalized‐ and precision medicine applications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Aims: Obesity is an important risk factor for severe acute pancreatitis. The necrosis of epididymal adipose tissue occurs in severe acute pancreatitis. Adipose tissue macrophages play an important role in metabolic related inflammation. Therefore, we explored the potential mechanisms between adipose tissue macrophages and obesity-related severe acute pancreatitis. Methods: Severe acute pancreatitis mice model was induced by caerulein with lipopolysaccharide. The severity of severe acute pancreatitis was evaluated according to the morphological, general, and biochemical change. We assessed the injury of epididymal white adipose tissue, pancreas, and adipose tissue macrophages in obese mice and lean mice with severe acute pancreatitis. Outcomes of caerulein-induced severe acute pancreatitis were studied in lean and obese mice with or without lipase inhibitor orlistat. Results: Fat necrosis and pancreatic injury increased in the SAP groups. High levels of serum free fatty acid and triglyceride were increased significantly in the SAP group. The NLRP3-caspase1 inflammasome signal pathway in adipose tissue macrophages markedly enhanced in the SAP groups compared with control group. Free fatty acid can trigger macrophages inflammation through NLRP3-caspase1. Lipase inhibited by orlistat remarkably decreased in adipose tissue necrosis, and the levels of serum lipase, amylase, and pancreatic tissue damage decreased in the orlistat group compared with the SAP group. The NLRP3-caspase1 inflammasome pathway in adipose tissue macrophages markedly decreased in the orlistat groups compared with SAP group. The levels of serum free fatty acid and triglyceride were decreased significantly in the orlistat group. Conclusions: Inflammation increases in adipose tissue macrophages of obese mice with severe acute pancreatitis. Free fatty acid generated via adipocyte lipolysis worsens inflammation in adipose tissue macrophages and the outcome of severe acute pancreatitis in obese mice through the NLRP3-caspase1 inflammasome pathway. [ABSTRACT FROM AUTHOR]

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.

Abstract Obesity exhibits a correlation with metabolic inflammation and endoplasmic reticulum stress, promoting the progression of metabolic disease such as diabetes, hyperlipidemia, hyperuricemia and so on. Adipose tissue macrophages (ATMs) are central players in obesity-associated inflammation and metabolic diseases. Macrophages are involved in lipid and energy metabolism and mitochondrial function in adipocytes. Macrophage polarization is accompanied by metabolic shifting between glycolysis and mitochondrial oxidative phosphorylation. Here, this review focuses on macrophage metabolism linked to functional phenotypes with an emphasis on macrophage polarization in adipose tissue physiological and pathophysiological processes. In particular, the interplay between ATMs and adipocytes in energy metabolism, glycolysis, OXPHOS, iron handing and even interactions with the nervous system have been reviewed. Overall, the understanding of protective and pathogenic roles of ATMs in adipose tissue can potentially provide strategies to prevent and treat obesity-related metabolic disorders.

Adipose tissue macrophages (ATMs) play important roles in maintaining adipose tissue homeostasis and orchestrating metabolic inflammation. Given the extensive functional heterogeneity and phenotypic plasticity of ATMs, identification of the authentically pathogenic ATM subpopulation under obese setting is thus necessitated. Herein, we performed single-nucleus RNA sequencing (snRNA-seq) and unraveled a unique maladaptive ATM subpopulation defined as ATF4 hi PDIA3 hi ACSL4 hi CCL2 hi inflammatory and metabolically activated macrophages (iMAMs), in which PDIA3 is required for the maintenance of their migratory and pro-inflammatory properties. Mechanistically, ATF4 serves as a metabolic stress sensor to transcribe PDIA3, which then imposes a redox control on RhoA activity and strengthens the pro-inflammatory and migratory properties of iMAMs through RhoA-YAP signaling. Administration of Pdia3 small interfering RNA (siRNA)-loaded liposomes effectively repressed adipose inflammation and high-fat diet (HFD)-induced obesity. Together, our data support that strategies aimed at targeting iMAMs by suppressing PDIA3 expression or activity could be a viable approach against obesity and metabolic disorders in clinical settings., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The prevalence of obesity is escalating and has become a worldwide health challenge coinciding with the development of metabolic diseases. Emerging evidence has shown that obesity is accompanied by the infiltration of macrophages into adipose tissue, contributing to a state of low-grade chronic inflammation and dysregulated metabolism. Moreover, in the state of obesity, the phenotype of adipose tissue macrophages switches from the M2 polarized state to the M1 state, thereby contributing to chronic inflammation. Notably, multiple metabolic organs (adipose tissue, gut, skeletal muscle, and the liver) communicate with adipose tissue macrophages via secreting organokines or exosomes. In this review, we systematically summarize how the organokines (adipokines, gut microbiota and its metabolites, gut cytokines, myokines, and hepatokines) and exosomes (adipocyte-, skeletal muscle-, and hepatocyte-derived exosomes) act as important triggers for macrophage recruitment in adipose tissue and adipose tissue macrophage polarization, thus providing further insight into obesity treatment. In addition, we also highlight the complex interaction of organokines with organokines and organokines with exosomes, revealing new paths in understanding adipose tissue macrophage recruitment and polarization.

The prevalence of obesity is escalating and has become a worldwide health challenge coinciding with the development of metabolic diseases. Emerging evidence has shown that obesity is accompanied by the infiltration of macrophages into adipose tissue, contributing to a state of low-grade chronic inflammation and dysregulated metabolism. Moreover, in the state of obesity, the phenotype of adipose tissue macrophages switches from the M2 polarized state to the M1 state, thereby contributing to chronic inflammation. Notably, multiple metabolic organs (adipose tissue, gut, skeletal muscle, and the liver) communicate with adipose tissue macrophages via secreting organokines or exosomes. In this review, we systematically summarize how the organokines (adipokines, gut microbiota and its metabolites, gut cytokines, myokines, and hepatokines) and exosomes (adipocyte-, skeletal muscle-, and hepatocyte-derived exosomes) act as important triggers for macrophage recruitment in adipose tissue and adipose tissue macrophage polarization, thus providing further insight into obesity treatment. In addition, we also highlight the complex interaction of organokines with organokines and organokines with exosomes, revealing new paths in understanding adipose tissue macrophage recruitment and polarization. [ABSTRACT FROM AUTHOR]

Excessive LDL cholesterol concentration together with subclinical inflammation, in which macrophages play a central role, are linked pathologies. The process starts with the accumulation of macrophages in white adipose tissue and the switch of their polarization toward a pro-inflammatory phenotype. The proportion of pro-inflammatory macrophages in adipose tissue is related to the main risk predictors of cardiovascular disease. The cholesterol content of phospholipids of cell membranes seems to possess a crucial role in the regulation of membrane signal transduction and macrophage polarization. Also, different fatty acids of membrane phospholipids influence phenotypes of adipose tissue macrophages with saturated fatty acids stimulating pro-inflammatory whereas ω3 fatty acids antiinflammatory changes. The inflammatory status of white adipose tissue, therefore, reflects not only adipose tissue volume but also adipose tissue macrophages feature. The beneficial dietary change leading to an atherogenic lipoprotein decrease may therefore synergically reduce adipose tissue driven inflammation. [ABSTRACT FROM AUTHOR]

Macrophages are involved in obesity-associated inflammation and severe acute pancreatitis (SAP) development. However, the role of adipose tissue macrophages (ATMs) in obesity-related SAP has not been fully elucidated. We investigated the relationship between ATMs and inflammatory responses in SAP model mice fed a high-fat diet (HFD). SAP was induced in animal models via intraperitoneal injections of caerulein and lipopolysaccharide (LPS). SAP severity was evaluated, both morphologically and biochemically, and macrophage infiltration in the pancreas and epididymal adipose tissue was measured. We also analyzed apoptosis levels, polarization of the ATMs, and expression of inflammatory mediators in epididymal adipose tissue. Obesity increased disease severity in SAP animals. Increased macrophage infiltration in the pancreas induced by SAP was found in both normal diet (ND)- and HFD-fed mice. Total ATM infiltration in epididymal adipose tissue was elevated by HFD, while a significant decrease in infiltration was observed in both the ND + SAP and HFD + SAP groups. The apoptosis levels of ATMs were reduced in the HFD group, but were markedly enhanced in both the ND + SAP and HFD + SAP groups compared to their respective control groups. Higher levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) were observed in the HFD + SAP than in the ND + SAP group. Increased proportion of M1 type ATMs was induced by both HFD and SAP. Total ATM infiltration was decreased in epididymal adipose tissue of SAP animals. ATM polarization to the M1 type resulted in an amplified inflammatory response in obese mice with SAP. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is a pregnancy-specific disease characterized by impaired glucose tolerance during pregnancy. Although diagnosis and clinical management have improved significantly, there are still areas where therapeutic approaches need further improvement. Recent evidence suggests that CCL2, a chemokine involved in immunoregulatory and inflammatory processes, is closely related to GDM. However, the potential value for clinical therapeutic applications and the mechanism of CCL2 in adipose tissue macrophages (ATMs) of GDM remain to be elucidated. Here, we found that CCL2 was enriched in macrophages of the visceral adipose tissue from GDM women and HFD-induced GDM mice. The combination of in vitro and in vivo experiments showed that Ccl2 silencing inhibited the inflammatory response of macrophage by blocking calcium transport between ER and mitochondria and reducing excessive ROS generation. Additionally, the ATS-9R/siCcl2 oligopeptide complex targeting adipose tissue was created. Under the delivery of ATS-9R peptide, Ccl2 siRNA is expressed in ATMs, which reduces inflammation in adipose tissue and, as a result, mitigates insulin resistance. All of these findings point to the possibility that the ATS-9R/siCcl2 complex, which targets adipose tissue, is able to reduce insulin resistance in GDM and the inflammatory response in macrophages. The ATS-9R/siCcl2 oligopeptide complex targeting adipose tissue seems to be a viable treatment for GDM pregnancies. [Display omitted] • ATS-9R delivers Ccl2 siRNA specifically to adipose tissue macrophages. • Ca2+ dependent mitochondrial ROS is reduced in Ccl2 silenced adipose tissue macrophages. • ATS-9R/siCcl2 complexes inhibit inflammatory response of adipose tissue macrophage. • ATS-9R/siCcl2 complexes benefit improving insulin resistance in GDM. [ABSTRACT FROM AUTHOR]

In obesity, high levels of saturated fatty acids (SFAs) contribute to adipose tissue inflammation and dysfunction. Obesity-induced macrophage infiltration leads to insulin resistance, but the adipocyte itself may play a role in generating the inflammatory milieu. Given our recent findings of the role of TLR4 in myeloid biasing in obesity, we next investigated the role of TLR4 in adipocyte generated inflammatory responses to SFAs and lipopolysaccharides. We used WT and Tlr4−/- ear mesenchymal stem cell derived adipocytes (EMSC Ad) and bone marrow dendritic cells (BMDCs) to evaluate cell specific responses. Our work demonstrates a role for TLR4 in adipocyte- immune cell crosstalk and that SFA derived metabolites from adipocytes may induce proinflammatory stimulation of immune cells in a TLR4 independent manner.

Adipose tissue macrophages (ATMs) represent the most abundant leukocytes in adipose tissue (AT). An increase in number and a phenotypical switch of ATMs during the development of obesity contribute to chronic inflammation and metabolic disorders, which have been regarded as potential therapeutic targets to restore AT homeostasis. Emodin has been shown to exert strong anti-inflammatory property via acting on macrophages in a range of disease models. However, whether emodin exerts a beneficial effect on obesity via modulating ATMs has not been reported. In high-fat diet (HFD)-induced obese mice, emodin significantly inhibited the increase of body weight and lipid accumulation in ATs. Emodin apparently reduced glucose and insulin levels and ameliorated serum lipid profiles in HFD-fed mice. Moreover, the local and systemic inflammation was dramatically alleviated by emodin. We next discovered that M2 macrophage percentage was greatly increased by emodin although total ATMs was not altered, which resulted in a net increase of M2 macrophages in AT. In vitro studies confirmed that emodin promoted the polarization of macrophages towards M2. Gene ontology (GO) analysis showed that myeloid leukocyte differentiation and activation were among the most significant biological processes in emodin-treated ATMs. We further identified that TREM2 was the most dramatically upregulated molecule by emodin and emodin-induced M2 macrophage polarization was dependent on TREM2. Furthermore, silencing TREM2 apparently abrogated the effect of emodin on AT inflammation and adipogenesis. We, for the first time, disclosed that emodin inhibited obesity by promoting M2 macrophage polarization via TREM2, suggesting that emodin may be explored as a clinical and translational candidate in preventing obesity and its related metabolic diseases. [ABSTRACT FROM AUTHOR]

“Inflammaging” refers to the chronic, low-grade inflammation that characterizes aging. Aging, like obesity, is associated with visceral adiposity and insulin resistance. Adipose tissue macrophages (ATMs) have played a major role in obesity-associated inflammation and insulin resistance. Macrophages are elevated in adipose tissue in aging. However, the changes and also possibly functions of ATMs in aging and aging-related diseases are unclear. In this review, we will summarize recent advances in research on the role of adipose tissue macrophages with aging-associated insulin resistance and discuss their potential therapeutic targets for preventing and treating aging and aging-related diseases. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) excess in bovine (b)GH transgenic mice has been shown to alter white adipose tissue (WAT) immune cell populations. The present study aimed to evaluate the effects of GH resistance on WAT immune cell populations using GH receptor knockout (GHR−/−) mice. Eight‐ and 24‐month‐old, male GHR−/− and wild‐type mice were used. Body composition and tissue weights were determined, and systemic inflammation was assessed by measuring serum cytokine levels. The stromal vascular fraction (SVF) was isolated from three distinct WAT depots, and immune cell populations were quantified using flow cytometry. GHR−/− mice at both ages had decreased body weight but were obese. Although no significant changes were observed in serum levels of the measured cytokines, SVF cell alterations were seen and differed from depot to depot. Total SVF cells were decreased in epidydimal (Epi) depots, whereas SVF cells per gram adipose tissue weight were increased in mesenteric (Mes) depots of GHR−/− mice relative to controls. T cells and T helper cells were increased in Mes at 8 months old, whereas cytotoxic T cells were decreased in subcutaneous (SubQ) at 24 months old. Other cells were unchanged at both ages measured. The present study demonstrates that removal of GH action results in modest and depot‐specific changes to several immune cell populations in WAT of intra‐abdominal depots (Epi and Mes), which are somewhat surprising results because the SubQ has the largest change in size, whereas the Mes has no size change. Taken together with previous results from bovine GH transgenic mice, these data suggest that GH induces changes in the immune cell population of WAT in a depot‐specific manner. Notably, GHR−/− mice appear to be protected from age‐related WAT inflammation and immune cell infiltration despite obesity. [ABSTRACT FROM AUTHOR]

Obesity‐induced activation and proliferation of resident macrophages and infiltration of circulating monocytes in adipose tissues contribute to adipose tissue inflammation and insulin resistance. These effects further promote the development of metabolic syndromes, such as type 2 diabetes, which is one of the most prevalent health conditions severely threatening human health worldwide. Our study examined the potential molecular mechanism employed by fibroblast growth factor 1 (FGF1) to improve insulin sensitivity. The leptin receptor‐deficient obese mice (db/db) served as an insulin‐resistant model. Our results demonstrated that FGF1‐induced amelioration of insulin resistance in obese mice was related to the decreased levels of pro‐inflammatory adipose tissue macrophages (ATMs) and plasma inflammatory factors. We found that FGF1 enhanced the adipocyte mTORC2/Rictor signalling pathway to inhibit C‐C chemokine ligand 2 (CCL2) production, the major cause of circulating monocytes infiltration, activation and proliferation of resident macrophages in adipose tissues. Conversely, these alleviating effects of FGF1 were substantially abrogated in adipocytes with reduced expression of mTORC2/rictor. Furthermore, a model of adipocyte‐specific mTORC2/Rictor‐knockout (AdRiKO) obese mice was developed to further understand the in vitro result. Altogether, these results demonstrated adipocyte mTORC2/Rictor was a crucial target for FGF1 function on adipose tissue inflammation and insulin sensitivity. [ABSTRACT FROM AUTHOR]

Obesity exhibits a correlation with metabolic inflammation and endoplasmic reticulum stress, promoting the progression of metabolic disease such as diabetes, hyperlipidemia, hyperuricemia and so on. Adipose tissue macrophages (ATMs) are central players in obesity-associated inflammation and metabolic diseases. Macrophages are involved in lipid and energy metabolism and mitochondrial function in adipocytes. Macrophage polarization is accompanied by metabolic shifting between glycolysis and mitochondrial oxidative phosphorylation. Here, this review focuses on macrophage metabolism linked to functional phenotypes with an emphasis on macrophage polarization in adipose tissue physiological and pathophysiological processes. In particular, the interplay between ATMs and adipocytes in energy metabolism, glycolysis, OXPHOS, iron handing and even interactions with the nervous system have been reviewed. Overall, the understanding of protective and pathogenic roles of ATMs in adipose tissue can potentially provide strategies to prevent and treat obesity-related metabolic disorders. [ABSTRACT FROM AUTHOR]

In mouse models, deficiency of TTC39B (T39) decreases hepatic lipogenic gene expression and protects against diet-induced steatohepatitis. While assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting T39, we discovered an unexpected weight loss phenotype. The objective of this study was to determine the mechanism of the resistance to diet-induced obesity. To assess therapeutic potential, we used antisense oligonucleotides (ASO) to knock down T39 expression in a Western or high-fat, high-cholesterol, high-sucrose-diet-fed Ldlr −/− or wild-type mice. T39 ASO treatment led to decreased hepatic lipogenic gene expression and decreased hepatic triglycerides. Unexpectedly, T39 ASO treatment protected against diet-induced obesity. The reduced weight gain was seen with two different ASOs that decreased T39 mRNA in adipose tissue macrophages (ATMs), but not with a liver-targeted GalNac-ASO. Mice treated with the T39 ASO displayed increased browning of gonadal white adipose tissue (gWAT) and evidence of increased lipolysis. However, T39 knockout mice displayed a similar weight loss response when treated with T39 ASO, indicating an off-target effect. RNA-seq analysis of gWAT showed a widespread increase in type I interferon (IFN)-responsive genes, and knockout of the IFN receptor abolished the weight loss phenotype induced by the T39 ASO. Some human T39 ASOs and ASOs with different modifications targeting LDLR also induced a type I IFN response in THP1 macrophages. Our data suggest that extrahepatic targeting of T39 by ASOs in ATMs produced an off-target type 1 IFN response, leading to activation of lipolysis, browning of WAT, and weight loss. While our findings suggest that ASOs may induce off-target type 1 IFN response more commonly than previously thought, they also suggest that therapeutic induction of type 1 IFN selectively in ATMs could potentially represent a novel approach to the treatment of obesity. • T39 ASOs produced an off-target type I IFN response resulting in reduced obesity, increased lipolysis and browning of WAT. • The resistance to diet-induced obesity and browning of white adipose tissue was dependent on IFNAR1. • Multiple ASOs produced a type I IFN response in vitro in human THP1 cells, suggesting they may be more common than suspected. • Therapeutic induction of low-grade type 1 IFN responses by ASO targeting to ATMs may represent a novel treatment for obesity. [ABSTRACT FROM AUTHOR]

Abstract Elevated concentrations of plasma fatty acids in transition dairy cows are significantly associated with increased disease susceptibility and poor lactation performance. The main source of plasma fatty acids throughout the transition period is lipolysis from adipose tissue depots. During this time, plasma fatty acids serve as a source of calories mitigating the negative energy balance prompted by copious milk synthesis and limited dry matter intake. Past research has demonstrated that lipolysis in the adipose organ is a complex process that includes not only the activation of lipolytic pathways in response to neural, hormonal, or paracrine stimuli, but also important changes in the structure and cellular distribution of the tissue in a process known as adipose tissue remodeling. This process involves an inflammatory response with immune cell migration, proliferation of the cellular components of the stromal vascular fraction, and changes in the extracellular matrix. This review summarizes current knowledge on lipolysis in dairy cattle, expands on the new field of adipose tissue remodeling, and discusses how these biological processes affect transition cow health and productivity.

Class 1 Phosphoinositide-3-Kinases (PI3Ks) have been widely studied and mediate essential roles in cellular proliferation, chemotaxis, insulin sensitivity, and immunity. Here, we provide a comprehensive overview of how macrophage expressed PI3Ks and their downstream pathways orchestrate responses to metabolic stimuli and nutrients, polarizing macrophages, shaping their cellular identity and function. Particular emphasis will be given to adipose tissue macrophages, crucial players of insulin resistance and chronic metabolically triggered inflammation during obesity. An understanding of PI3K dependent wiring of macrophage responses is important as this is involved in various diseases ranging from obesity, type 2 diabetes to chronic inflammatory disease.

Obesity is a growing epidemic in the United States and worldwide and is associated with insulin resistance and cardiovascular disease, among other comorbidities. Understanding of the pathology that links overnutrition to these disease processes is ongoing. Adipose tissue is a heterogeneous organ comprised of multiple different cell types and it is likely that dysregulated metabolism within these cell populations disrupts both inter- and intracellular interactions and is a key driver of human disease. In recent years, metabolic flux analysis, which offers a precise quantification of metabolic pathway fluxes in biological systems, has emerged as a candidate strategy for uncovering the metabolic changes that stoke these disease processes. In this mini review, we discuss metabolic flux analysis as an experimental tool, with a specific emphasis on mass spectrometry with isotope tracing as this is the technique most frequently used for metabolic flux analysis in adipocytes. Furthermore, we examine existing literature that uses metabolic flux analysis to further our understanding of adipose tissue biology. Our group has a specific interest in understanding the role of white adipose tissue inflammation in the progression of cardiometabolic disease, as we know that in obesity the accumulation of pro-inflammatory adipose tissue macrophages is associated with significant morbidity, so we use this as a paradigm throughout our review for framing the application of these experimental techniques. However, there are many other biological applications to which they can be applied to further understanding of not only adipose tissue biology but also systemic homeostasis., Competing Interests: A.M. and J.B. declare no conflicts of interest. J.O.A. is currently acting as a consultant for Novo Nordisk and formerly served as a chair on Novo Nordisk’s Data and Safety Monitoring Board without compensation., (Copyright © 2024 The Author(s), Published by Wolters Kluwer Health, Inc.)

• HFD induced obesity, dramatic fat expansion, and accumulation of ATMs in mice. • HFD-induced changes in VAT were partially reversed upon reverting to ND for 6 weeks. • Transient reduction of blood monocyte count was seen at early stages of HFD feeding. • Blood monocytes could be targeted as a new obesity treatment. Infiltration of adipose tissue macrophages (ATMs) is a typical feature of obesity, and circulating immune cells may indicate immune cell accumulation. However, it remains unclear whether this is true in the early stages of obesity. This study aimed to define the role of blood monocytes in obesity and the relationship between blood monocytes and ATMs in early-stage obesity. Two groups of male C57BL/6 J mice were fed on a 60 % high-fat diet (HFD) or a 10 % fat normal diet (ND), respectively, and monitored at 1, 2, 3, 7, and 12 weeks. Populations of circulating blood monocytes (CD11b + CD115+), ATMs (F4/80+CD11b+), and their subtypes were collected and analyzed using flow cytometry and immunofluorescence. Some cytokines (TNF-a, IL-1β) and chemokines (CCL2, CCL7) were also analyzed by real-time PCR. HFD induced obesity, dramatic fat expansion, and accumulation of ATMs in mice after 12 weeks. However, an acute and transient reduction of circulating monocyte count, elevated expression of CD11c in ly6clow monocytes, and concurrent infiltration of ATMs into visceral adipose tissues (VAT) were observed as early as 1 week after initiating HFD. Further, HFD-induced changes in VAT, but not blood monocyte count, were partially reversed upon reverting to ND for 6 weeks. An acute but transient reduction of blood monocyte count was observed at the early stages of HFD feeding, which might be related to early infiltration of macrophages into adipose tissues. We believe that blood monocytes could be targeted as a new obesity treatment following additional studies. [ABSTRACT FROM AUTHOR]

In obesity, high levels of saturated fatty acids (SFAs) contribute to adipose tissue inflammation and dysfunction. Obesity-induced macrophage infiltration leads to insulin resistance, but the adipocyte itself may play a role in generating the inflammatory milieu. Given our recent findings of the role of TLR4 in myeloid biasing in obesity, we next investigated the role of TLR4 in adipocyte generated inflammatory responses to SFAs and lipopolysaccharides. We used WT and Tlr4-/- ear mesenchymal stem cell derived adipocytes (EMSC Ad) and bone marrow dendritic cells (BMDCs) to evaluate cell specific responses. Our work demonstrates a role for TLR4 in adipocyteimmune cell crosstalk and that SFA derived metabolites from adipocytes may induce proinflammatory stimulation of immune cells in a TLR4 independent manner. [ABSTRACT FROM AUTHOR]

This study investigated the role of microRNAs generated from adipose tissue macrophages (ATMs) during adipose tissue remodeling induced by pharmacological and nutritional stimuli. Macrophage-specific Dicer knockout (KO) mice were used to determine the roles of microRNA generated in macrophages in adipose tissue remodeling induced by the β3-adrenergic receptor agonist CL316,243 (CL). RNA-seq was performed to characterize microRNA and mRNA expression profiles in isolated macrophages and PDGFRα+ adipocyte stem cells (ASCs). The role of miR-10a-5p was further investigated in cell culture, and in adipose tissue remodeling induced by CL treatment and high fat feeding. Macrophage-specific deletion of Dicer elevated pro-inflammatory gene expression and prevented CL-induced de novo beige adipogenesis in gonadal white adipose tissue (gWAT). Co-culture of ASCs with ATMs of wild type mice promoted brown adipocyte gene expression upon differentiation, but co-culture with ATMs of Dicer KO mice did not. Bioinformatic analysis of RNA expression profiles identified miR-10a-5p as a potential regulator of inflammation and differentiation in ATMs and ASCs, respectively. CL treatment increased levels of miR-10a-5p in ATMs and ASCs in gWAT. Interestingly, CL treatment elevated levels of pre-mir-10a in ATMs but not in ASCs, suggesting possible transfer from ATMs to ASCs. Elevating miR-10a-5p levels inhibited proinflammatory gene expression in cultured RAW 264.7 macrophages and promoted the differentiation of C3H10T1/2 cells into brown adipocytes. Furthermore, treatment with a miR-10a-5p mimic in vivo rescued CL-induced beige adipogenesis in Dicer KO mice. High fat feeding reduced miR-10a-5p levels in ATMs of gWAT, and treatment of mice with a miR-10a-5p mimic suppressed pro-inflammatory responses, promoted the appearance of new white adipocytes in gWAT, and improved systemic glucose tolerance. These results demonstrate an important role of macrophage-generated microRNAs in adipogenic niches and identify miR-10a-5p as a key regulator that reduces adipose tissue inflammation and promotes therapeutic adipogenesis. • Macrophage-specific Dicer KO prevented CL-induced beige adipogenesis in gWAT. • Bioinfomatic analysis of RNAseq identified miR-10a-5p as a key player in AT remodeling. • CL treatment upregulated miR-10a-5p in AT macrophages and in activated ASCs. • miR-10a-5p promoted beige adipogenesis in vivo and in vitro , in part by targeting Rora. • miR-10a-5p treatment reduced HFD-induced inflammation and improved glucose tolerance. [ABSTRACT FROM AUTHOR]

Dysfunction of the adipose tissue is a central driver for obesity‐associated diabetes. It is characterized by dysregulated adipokine secretion, which contributes to insulin resistance of key metabolic tissues, including the liver, skeletal muscles, and fat itself. The inter‐organ cross talk between the adipose tissue and the other organs as well as the intra‐organ cross talk between adipocytes and macrophages within the adipose tissue, traditionally mediated by hormones, was recently evidenced to be regulated by adipose‐derived exosomes. Exosomes are nano‐sized membrane‐bound vesicles secreted by the donor cells to modify intercellular communication by translating constituent nucleic acids and proteins to the target cells. Herein, we reviewed the latest progress in understanding the role of adipose‐derived exosomes in the development of insulin resistance, a key mechanism that underpins diabetes and diabetic complications, with a special focus on the role of exosomal miRNAs (micro RNAs) and proteins, and discusses the potential implications of targeting adipose tissue‐derived exosomes for diabetic therapeutics. [ABSTRACT FROM AUTHOR]

Previously, we showed that loss of ovarian function in mice fed high-fat diet exacerbated insulin resistance and adipose tissue inflammation. In the current study, we tested whether consumption of luteolin, an anti-inflammatory flavonoid, could mitigate adipose tissue inflammation and insulin resistance in obese ovariectomized mice. Nine-week-old ovariectomized C57BL/6 mice were fed a low-fat diet, high-fat diet (HFD) or HFD supplemented with 0.005% luteolin (HFD+L) for 16 weeks. Results showed no difference in body weight or fat mass between mice fed HFD+L and those fed HFD. However, luteolin supplementation resulted in lower CD11c+ macrophages in gonadal adipose tissue, as well as a trend toward lower macrophage infiltration. Luteolin supplementation also significantly lowered mRNA expression of inflammatory and M1 markers MCP-1, CD11c, TNF-α and IL-6, while maintaining expression of M2 marker MGL1. Consistent with this, the in vitro luteolin treatment, with or without the presence of estrogen, inhibited lipopolysaccharide-induced polarization of RAW 264.7 cells toward M1 phenotype. We further found that luteolin supplementation protected mice from insulin resistance induced by HFD consumption; this improved insulin resistance was correlated with reductions in CD11c+ adipose tissue macrophages. Taken together, these findings indicate that dietary luteolin supplementation attenuates adipose tissue inflammation and insulin resistance found in mice with loss of ovarian function coupled with an HFD intake, and this effect may be partly mediated through suppressing M1-like polarization of macrophages in adipose tissue. These results have clinical implication in implementing dietary intervention for prevention of metabolic syndrome associated with postmenopause and obesity. [ABSTRACT FROM AUTHOR]

Macrophages infiltration in adipose tissue is associated with obesity-induced inflammation and insulin resistance. In lean adipose tissue.the number of M2 macrophages is predominant and M2 macrophages play a role in adipose tissue homeostasis. During obesity. Ml macrophages are dramatically increased in number and secrete pro-inflammatory cytokines, leading to adipose tissue inflammation and insulin resistance. Thus, macrophage-induced inflammation is thought to be a link between obesity and obesity-related metabolic syndrome. This review summarizes the role of adipose tissue macrophages in the pathogenesis of obesity-induced inflammation and insulin resistance. [ABSTRACT FROM AUTHOR]

Adipose tissue macrophages (ATMs) in obesity and asthma. Inhibition of sEHi reduced systemic inflammation by inhibiting M1-type macrophage polarization and facilitating M2-type macrophage polarization in ATMs, thereby alleviating obese asthma. [Display omitted] Obesity increases the risk of asthma 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 adipose tissue macrophages (ATMs) that could contribute to a low-grade inflammation state. 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 tumor necrosis factor-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. [ABSTRACT FROM AUTHOR]