Macrophage polarization plays a pivotal role in immune homeostasis and disease progression across inflammatory, neoplastic, and metabolic disorders. Saponins, which are natural compounds with steroidal/triterpenoid structures, demonstrate therapeutic potential through immunomodulatory, anti-inflammatory, and anti-tumor activities. This study aims to highlight the potential of key saponins-such as ginsenosides, astragaloside IV, dioscin, platycodin D, pulsatilla saponins, and panax notoginseng saponins-in modulating macrophage polarization and enhancing conventional therapies, particularly in oncology. We conducted structured searches in PubMed, Google Scholar, and SciFinder (2013-2024) using controlled vocabulary, including "saponins," "macrophage polarization," and "therapeutic effects." Our findings demonstrate that saponins significantly modulate immune responses and improve treatment efficacy. However, clinical translation is hindered by challenges such as poor bioavailability and safety concerns, which limit systemic exposure and therapeutic utility. To overcome these barriers, innovative delivery strategies, including nanoemulsions and engineered exosomes, are essential for enhancing pharmacokinetics and therapeutic index. Future research should prioritize elucidating the molecular mechanisms underlying saponin-mediated macrophage polarization, identifying novel therapeutic targets, and optimizing drug formulations. Addressing these challenges will enable the restoration of immune balance and more effective management of diverse diseases.

Obesity-associated inflammation is characterized by macrophage infiltration into peripheral tissues, contributing to the progression of prediabetes and type 2 diabetes. 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids and promotes the migration of macrophages, yet its role in obesity-associated inflammation remains incompletely understood. Furthermore, differences between mouse and human orthologs of 12-LOX have limited efforts to study existing pharmacologic inhibitors of 12-LOX. In this study, we used a human gene replacement mouse model in which the gene encoding mouse 12-LOX (Alox15) is replaced by the human ALOX12 gene. As a model of obesity and dysglycemia, we administered male mice a high-fat diet. We subsequently investigated the effects of VLX-1005, a potent and selective small molecule inhibitor of human 12-LOX. Oral administration of VLX-1005 resulted in improved glucose homeostasis, decreased β-cell dedifferentiation, and reduced macrophage infiltration in islets and adipose tissue. Analysis of the stromal vascular fraction from adipose tissue showed a reduction in myeloid cells and cytokine expression with VLX-1005 treatment, indicating decreased adipose tissue inflammation. In a distinct mouse model in which Alox15 was selectively deleted in myeloid cells, we observed decreased β-cell dedifferentiation and reduced macrophage infiltration in both islets and adipose tissue, suggesting that the effects of VLX-1005 may relate to the inhibition of 12-LOX in macrophages. These findings highlight 12-LOX as a key factor in obesity-associated inflammation and suggest that 12-LOX inhibition could serve as a therapeutic strategy to improve glucose homeostasis and peripheral inflammation in the setting of obesity and type 2 diabetes.

Over-nutrition and lipid metabolic abnormalities are correlated with obesity and type 2 diabetes mellitus (T2DM). Individuals with long-term hyperglycemia and dyslipidemia are susceptible to life-threatening complications such as atherosclerosis. Excess amounts of modified low density lipoprotein (mLDL) attract circulating monocytes to resident at arterial wall and differentiate into pro-inflammatory M1 macrophages. M1 cells uptake mLDL through scavenger receptors-mediated endocytosis, leading to increased lipids influx, cholesterol accumulation and foam cell formation. Besides, macrophages are attracted and infiltrated into the hypertrophic adipose tissue to mediate microenvironmental lipid metabolism. Our previous studies demonstrate that anti-inflammatory interleukin-4 (IL-4) regulates lipid metabolism by inhibiting lipid accumulation and promoting lipolysis of mature adipocytes. The effects of IL-4-polarized M2 macrophages on 3T3-L1 adipogenesis and macrophage-adipocyte interaction were explored in the present study. Our results showed lipid deposits and lipid droplets (LDs)-anchored perilipin of adipocytes cultured in IL-4-polarized M2-conditioned medium (M2-CM) were decreased, while adipogenesis-driving transcription factors and critical lipid metabolic enzymes remained unaffected. It indicates that M2-secreted mediators down-regulate lipid deposits and LDs formation in late adipogenic phase rather than interfering early programming phase and lipid synthesis machinery. In addition, IL-4 reduced intracellular lipid loads by up-regulating cholesterol efflux ATP-binding cassette transporter A1 (ABCA1) and ABCG1 despite cholesterol influx CD36 was also elevated. Accordingly, IL-4 shows beneficial effects to prevent atherosclerosis via promoting catabolism of the internalized lipids and cholesterol efflux, thus efficiently reduces lipid overload and foam cell formation. These findings illustrate novel roles and protective function of IL-4 to reduce the risk of atherosclerosis incidence by efficiently promoting macrophage cholesterol efflux and lipid homeostasis.

Physiological processes, including metabolism and immune responses, are generated by the circadian clock, driven by clock genes. Disrupting circadian rhythms through a high-fat diet promotes obesity and inflammation. Studies show that deleting the clock gene, brain, and muscle ARNT-like 1 (Bmal1) in adipose tissue leads to overeating and weight gain. We now show that Bmal1 deletion in neutrophils protects against diet-induced obesity and reduces inflammatory macrophage infiltration into epididymal white adipose tissue (eWAT), despite increased food intake over 20 weeks of a high-fat diet. This protection is linked to enhanced energy expenditure, increased UCP1 expression in iBAT, improved insulin sensitivity, and altered expression of genes encoding chemokine receptors CXCR2, CXCR4, and the ligand Cxcl2 in eWAT. Our findings reveal a key role of Bmal1 in neutrophils in regulating high-fat diet-induced adipose inflammation and emphasize circadian regulation's importance in immuno-metabolic function.

Ectopic lipid accumulation in macrophages is responsible for the formation of macrophage foam cells (MFCs) which are involved in the crosstalk with the perivascular adipose tissue (PVAT) of the vascular wall that plays a pivotal role in the progression of atherosclerosis. However, the interrelationship between MFCs and PVAT implementing adipocyte dysfunction during atherosclerosis has not yet been established. We hypothesized that MFC-secreted mediator(s) is causally linked with PVAT dysfunction and the succession of atherosclerosis. To test this hypothesis, MFCs were cocultured with adipocytes, or the conditional media of MFCs (MFC-CM) were exposed to adipocytes and found a significant induction of fat lipolysis in adipocytes. The molecular filtration followed by the high-performance liquid chromatography (HPLC) fractionation and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) analysis of MFC-CM revealed a novel mediator fetuin-A (FetA) that significantly augments toll-like receptor 4 (TLR4)-dependent fat lipolysis in adipocytes. Mechanistically, MFC-derived FetA markedly increased TLR4-dependent c-Jun N-terminal kinases (JNK)/extracellular signal-regulated kinases (ERK) activation that causes spontaneous fat lipolysis implementing adipocyte dysfunction. Thus, the present study provides the first evidence of MFC-derived FetA that induces adipocyte dysfunction by the stimulation of spontaneous fat lipolysis. Therefore, targeting the crosstalk between MFCs and adipocytes could be a newer approach to counter the progression of atherosclerosis.

Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.

Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) and its progressive form, Metabolic Dysfunction Associated Steatohepatitis (MASH), represent significant health concerns associated with the metabolic syndrome. These conditions are characterized by excessive hepatic fat accumulation, inflammation, and potential progression to cirrhosis and hepatocellular carcinoma. Neutrophils are innate immune cells that play a pivotal role in the development of MASLD and MASH. They can infiltrate the hepatic microenvironment in response to inflammatory cytokines and damage associated molecular patterns (DAMPs) derived from the liver and exacerbate tissue damage by releasing of reactive oxygen species (ROS), cytokines, and neutrophil extracellular traps (NETs). Moreover, neutrophils can disrupt the metabolism of hepatocytes through key factors such as neutrophil elastase (NE) and human neutrophil peptides-1 (HNP-1), leading to inflammation and fibrosis, while myeloperoxidase (MPO) and lipocalin (LCN2) are involved in inflammatory and fibrotic processes. In contrast, neutrophils contribute to liver protection and repair through mechanisms involving microRNA-223 and matrix metalloproteinase 9 (MMP9). This dual role of neutrophils highlights their significance in the pathogenesis of MASLD and MASH. This review summarizes current understanding from recent studies on the involvement of neutrophils in MASLD and MASH. Understanding complex roles of neutrophils within the liver's unique microenvironment offers insights into novel therapeutic strategies, emphasizing the need for further research to explore neutrophil-targeted interventions for managing MASLD and MASH. [BMB Reports 2025; 58(3): 116-123].

Synovium is home to immune and stromal cell types that orchestrate inflammation following a joint injury; in particular, macrophages are central protagonists in this process. We sought to define the cellular and temporal dynamics of the synovial immune niche in a mouse model of post-traumatic osteoarthritis (PTOA), and to identify stromal-immune crosstalk mechanisms that coordinate macrophage function and phenotype. We induced PTOA in mice using a non-invasive tibial compression model of anterior cruciate ligament rupture (ACLR). Single-cell RNA-sequencing and flow cytometry were used to assess immune cell populations in healthy (Sham) and injured (7 and 28 days post-ACLR) synovium. Characterization of synovial macrophage polarization states was performed, alongside computational modeling of macrophage differentiation, as well as implicated transcriptional regulators and stromal-immune communication axes. Immune cell types are broadly represented in healthy synovium, but experience drastic expansion and speciation in PTOA, most notably in the macrophage portion. We identified several polarization states of macrophages in synovium following joint injury, underpinned by distinct transcriptomic signatures, and regulated in part by stromal-derived macrophage colony-stimulating factor signaling. The transcription factors Pu.1, Cebpα, Cebpβ, and Jun were predicted to control differentiation of systemically derived monocytes into pro-inflammatory synovial macrophages. In summary, we defined different synovial macrophage subpopulations present in healthy and injured mouse synovium. Nuanced characterization of the distinct functions, origins, and disease kinetics of macrophage subtypes in PTOA will be critical for targeting these highly versatile cells for therapeutic purposes.

Brown adipose tissue (BAT) and thermogenic beige fat within white adipose tissue (WAT), collectively known as adaptive thermogenic fat, dissipate energy as heat, offering promising therapeutic potential to combat obesity and metabolic disorders. The specific biological functions of these fat depots are determined by their unique interaction with the microenvironments, composed of immune cells, endothelial cells, pericytes, and nerve fibers. Immune cells residing in these depots play a key role in regulating energy expenditure and systemic energy homeostasis. The dynamic microenvironment of thermogenic fat depots is essential for maintaining tissue health and function. Immune cells infiltrate both BAT and beige WAT, contributing to their homeostasis and activation through intricate cellular communications. Emerging evidence underscores the importance of various immune cell populations in regulating thermogenic adipose tissue, though many remain undercharacterized. This review provides a comprehensive overview of the immune cells that regulate adaptive thermogenesis and their complex interactions within the adipose niche, highlighting their potential to influence metabolic health and contribute to therapeutic interventions for obesity and metabolic syndrome.

Obesity is a metabolic disease resulting from excess body fat accumulation associated with chronic systemic inflammation. Obesity has been shown to impact the function and activity of neutrophils, macrophages, and T cells, contributing to higher circulating levels of pro-inflammatory cytokines. Biomaterial surface properties such as roughness and hydrophilicity can influence the behavior of immune cells in the peri-implant microenvironment. This study aimed to determine how obesity induced by a high-fat diet (HFD) affects the inflammatory response to modified titanium (Ti) implants and subsequent bone formation. Obese mice had significantly more neutrophils, pro-inflammatory macrophages, and T cells and fewer anti-inflammatory macrophages and mesenchymal stem cells (MSCs) in the peri-implant tissue than lean mice. Obesity also increased circulating adipokines and pro-inflammatory cytokines when compared to lean animals. Bone formation around Ti implants was reduced in obese mice compared to controls. Adoptive transfer of bone marrow cells isolated from obese mice into wild-type mice demonstrated the localized impact of obesity on immune cell function and phenotype, promoting a pro-inflammatory peri-implant microenvironment and attenuating bone formation post-implantation. These results show that obesity significantly affects the inflammatory response to modified Ti implants, prolonging the pro-inflammatory response to the implanted biomaterial and compromising bone formation. STATEMENT OF SIGNIFICANCE: Obesity has been shown to significantly alter physiological processes, including the behavior of immune cells, inducing a state of systemic chronic inflammation. Our study demonstrates that obesity-induced via a high-fat diet alters immune cell response to implanted biomaterials, with increased pro-inflammatory response and attenuated immunomodulation that results in decreased biomaterial integration.

Obesity-associated inflammation is characterized by macrophage infiltration into peripheral tissues, contributing to the progression of prediabetes and type 2 diabetes (T2D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids and is known to promote the migration of macrophages, yet its role in obesity-associated inflammation remains incompletely understood. Furthermore, differences between mouse and human orthologs of 12-LOX have limited efforts to study existing pharmacologic inhibitors of 12-LOX. In this study, we utilized a human gene replacement mouse model in which the gene encoding mouse 12-LOX (Alox15) is replaced by the human ALOX12 gene. As a model of obesity and dysglycemia, we administered these mice a high-fat diet. We subsequently investigated the effects of VLX-1005, a potent and selective small molecule inhibitor of human 12-LOX. Oral administration of VLX-1005 resulted in improved glucose homeostasis, decreased β cell dedifferentiation, and reduced macrophage infiltration in islets and adipose tissue. Analysis of the stromal vascular fraction from adipose tissue showed a reduction in myeloid cells and cytokine expression with VLX-1005 treatment, indicating decreased adipose tissue inflammation. In a distinct mouse model in which Alox15 was selectively deleted in myeloid cells, we observed decreased β cell dedifferentiation and reduced macrophage infiltration in both islets and adipose tissue, suggesting that the effects of VLX-1005 may relate to the inhibition of 12-LOX in macrophages. These findings highlight 12-LOX as a key factor in obesity-associated inflammation and suggest that 12-LOX inhibition could serve as a therapeutic strategy to improve glucose homeostasis and peripheral inflammation in the setting of obesity and T2D.

Glucose transporter 4 (GLUT4) expression on white adipocytes is critical for absorbing excess blood glucose, failure of which promotes hyperglycemia. Matrix metalloproteinases (MMPs) play a crucial role in remodeling the white adipose tissue (WAT) during obesity. MMPs have multiple protein substrates, and surprisingly, it is unknown if they can directly target GLUT4 on the adipocyte surface and impair glucose absorption. We identified MMP2 as the highly active gelatinase, a class of MMP, in the gonadal WAT of high-fat diet-induced obese mice. In vitro, metabolic studies in 3T3-L1 adipocytes revealed MMP2 attenuated glucose absorption and glycolysis, which were recovered by an MMP2 inhibitor. In silico structural analysis using AlphaFold identified a putative MMP2 cleavage site on the extracellular domain of GLUT4. Further, in a substrate competition assay, a peptide mimicking the MMP2 cleavage motif on GLUT4 attenuated the cleavage of an MMP substrate by MMP2. Altogether, our results suggest a novel mechanism of impaired glucose absorption by adipocytes, which may contribute to hyperglycemia during obesity.

Vasculopathy underlies diabetic complications, with perivascular adipose tissue (PVAT) playing crucial roles in its development. However, the changes in the cellular composition and function of PVAT, including the specific cell subsets and mechanisms implicated in type 2 diabetes mellitus (T2DM) vasculopathy, remain unclear.

To address the above issues, we performed single-cell RNA sequencing on the stromal vascular fraction (SVF) of PVAT from normal and T2DM rats. Then, various bioinformatics tools and functional experiments were used to investigate the characteristic changes in the cellular profile of diabetic PVAT SVF, their implications, and the underlying mechanisms.

Our study reveals the single-cell landscape of the SVF of PVAT, demonstrating its considerable heterogeneity and significant alterations in T2DM, including an enhanced inflammatory response and elevated proportions of macrophages and natural killer (NK) cells. Moreover, macrophages are critical hubs for cross-talk among various cell populations. Notably, we identified a decreased Pdpn+ macrophage subpopulation in the PVAT of T2DM rats and confirmed this in mice and humans. In vitro and in vivo studies demonstrated that Pdpn+ macrophages alleviated insulin resistance and modulated adipokine/cytokine expression in adipocytes via the Pla2g2d-DHA/EPA-GPR120 pathway. This subset also enhances the function of vascular endothelial and smooth muscle cells, inhibits vascular inflammation and oxidative stress, and improves vasodilatory function, thereby protecting blood vessels.

Pdpn+ macrophages exhibit significant vascular protective effects by alleviating insulin resistance and modulating adipokine/cytokine expression in PVAT adipocytes. This macrophage subtype may therefore play pivotal roles in mitigating vascular complications in T2DM. Our findings also underscore the critical role of immune-metabolic cross-talk in maintaining tissue homeostasis.

Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (Mir802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of Mir802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of Mir802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of Mir802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, Mir802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokines and SREBP1, leading to strong recruitment and M1-like polarization of macrophages. Our findings indicate that Mir802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores Mir802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.

Macrophages in obese adipose tissue have been shown to damage nerve fibers, however, the mechanism underlying how macrophages cause glial cell damage remains unknown. This study aimed to characterize the mechanism by which macrophages induce apoptosis in glial cell during obesity formation in mice by single-nucleus RNA sequencing (snRNA-seq). Cells obtained from paraepididymal adipose tissue in obese mice underwent snRNA-seq. Eighteen different clusters were identified, and 12 cell types were annotated, including glial cells, macrophages, and fibroblasts. There was a negative correlation between the number of glial cells and macrophages in mouse adipose tissue during the formation of obesity. The pro-apoptotic factor PHLPP1 was identified in GO Terms. The interaction between adipose tissue glial cells and macrophages was revealed via in-depth analysis, and the cell-cell communication mechanism between the TNF-α and NF-KB/PHLPP1 axes was perfected. Apoptosis of glial cell by upregulation of TNF-α via obesity-derived macrophages and activation of the NF-κB/PHLPP1 axis. We further revealed how macrophages induce apoptosis in glial cells during obesity formation, as well as different changes in the two cell populations. This study provides valuable resources and foundations for understanding the mechanistic effects of macrophages and glial cells during obesity formation, as well as diseases and potential interventions.

Obesity is associated with an increased risk for 13 different cancers. The increased risk for cancer in obesity is mediated by obesity-associated changes in the immune system. Obesity has distinct effects on different types of inflammation that are tied to tumorigenesis. For example, obesity promotes chronic inflammation in adipose tissue that is tumor-promoting in peripheral tissues. Conversely, obesity inhibits acute inflammation that rejects tumors. Obesity therefore promotes cancer by differentially regulating chronic versus acute inflammation. Given that obesity is chronic, the initial inflammation in adipose tissue will lead to systemic inflammation that could induce compensatory anti-inflammatory reactions in peripheral tissues to suppress chronic inflammation. The overall effect of obesity in peripheral tissues is therefore dependent on the duration and severity of obesity. Adipose tissue is a complex tissue that is composed of many cell types in addition to adipocytes. Further, adipose tissue cellularity is different at different anatomical sites throughout the body. Consequently, the sensitivity of adipose tissue to obesity is dependent on the anatomical location of the adipose depot. For example, obesity induces more inflammation in visceral than subcutaneous adipose tissue. Based on these studies, the mechanisms by which obesity promotes tumorigenesis are multifactorial and immune cell type-specific. The objective of our paper is to discuss the cellular mechanisms by which obesity promotes tumorigenesis by regulating distinct types of inflammation in adipose tissue and the tumor microenvironment.

Radix scutellariae (the root of Scutellaria baicalensis Georgi) is a traditional Chinese medicine (TCM) used to treat a wide range of inflammation-related diseases, such as obesity, diabetes, diabetic kidney disease, and COVID-19-associated inflammatory states in the lung and kidney. Baicalin is the major anti-inflammatory component of Radix scutellariae and has shown the potential to inhibit inflammation in metabolic disorders. In this study, we explored the ability and underlying mechanisms of baicalin to modulate the macrophage to mitigate insulin resistance in obesity.

Obese mice were administered baicalin (50 mg/kg/day) intraperitoneally for 3 weeks. RAW264.7 and BMDM cells were stimulated with LPS and treated with baicalin for 24 h, while 3T3-L1 and primary white adipocytes were treated with the supernatants from baicalin-treated RAW264.7 cells for 24 h.

The results showed that baicalin significantly improved glucose and insulin tolerance as well as decreased fat and adipose tissue macrophage levels in obese mice. Besides, baicalin significantly reduced serum and adipose tissue IL-1β, TNF-α and IL-6 levels in obese mice, as well as suppressed LPS-induced IL-1β, TNF-α and IL-6 expression and release in macrophages. Furthermore, treatment with the supernatant from baicalin-treated RAW264.7 cells increased the levels of PGC-1α, SIRT1, p-IRS-1 and p-AKT in adipocytes. Moreover, baicalin treatment dramatically downregulated macrophage p-p38, p-JNK, and Ac-p65Lys310 levels while increasing SIRT1 both in vivo and in vitro. Importantly, JNK inhibitor SP600125 blocked most of the effects of baicalin on SIRT1, Ac-p65Lys310 and pro-inflammatory factors in macrophages.

Therefore, these results demonstrated for the first time that baicalin exerts its anti-inflammatory effects in obese adipose tissue macrophages mainly through suppressing JNK/SIRT1/p65 signaling. These findings amplified the mechanisms of baicalin and its potential to attenuate insulin resistance.

Despite numerous studies confirming the association between insulin resistance (IR) and macrophage polarization, there is a lack of bibliometric analysis in this area. Therefore, our objective is to conduct a comprehensive analysis of published literature and identify potential future research trends using bibliometrics.

Publications on the topic of macrophage polarization in IR were gathered from the Web of Science Core Collection database (WoSCC) spanning the years 1999-2023. Bibliometric analysis and visualization were conducted using VOSviewers, CiteSpace, the R package "bibliometrix" and Tableau Public.

A total of 3435 articles published between 1999 and 2023 were included in the analysis. These articles originated from 75 countries, with the United States and China leading in contributions. The top five research institutions are the University of California, San Diego, Harvard University, the University of Michigan, Shanghai Jiao Tong University, and Huazhong University of Science and Technology. In this research domain, Diabetes is the most frequently published journal, and the Journal of Clinical Investigation is the most co-cited. Among the 19,398 authors contributing to these publications, Lumeng CN. not only authored the most papers but also received the highest number of co-citations. "Insulin resistance" emerges as a primary keyword in the analysis of emerging research hotspots.

For the first time, bibliometric methods have been employed to conduct a comprehensive summary of papers relevant to macrophage polarization in IR. This study aims to identify the current research direction and future research hotspots, offering valuable guidance and insights for scholars in the field.

Adipose tissue macrophages (ATMs) are key regulators of adipose tissue (AT) inflammation and insulin resistance in obesity, and the traditional M1/M2 characterization of ATMs is inadequate for capturing their diversity in obese conditions. Single-cell transcriptomic profiling has revealed heterogeneity among ATMs that goes beyond the old paradigm and identified new subsets with unique functions. Furthermore, explorations of their developmental origins suggest that multiple differentiation pathways contribute to ATM variety. These advances raise concerns about how to define ATM functions, how they are regulated, and how they orchestrate changes in AT. This review provides an overview of the current understanding of ATMs and their updated categorization in both mice and humans during obesity. Additionally, diverse ATM functions and contributions in the context of obesity are discussed. Finally, potential strategies for targeting ATM functions as therapeutic interventions for obesity-induced metabolic diseases are addressed.

Obesity disrupts glucose metabolism, leading to insulin resistance (IR) and cardiometabolic diseases. Consumption of cow's milk and other dairy products may influence glucose metabolism. Within the complex matrix of cow's milk, various carbohydrates, lipids, and peptides act as bioactive molecules to alter human metabolism. Here, we summarize data from human studies and rodent experiments illustrating how these bioactive molecules regulate insulin and glucose homeostasis, supplemented with in vitro studies of the mechanisms behind their effects. Bioactive carbohydrates, including lactose, galactose, and oligosaccharides, generally reduce hyperglycemia, possibly by preventing gut microbiota dysbiosis. Milk-derived lipids of the milk fat globular membrane improve activation of insulin signaling pathways in animal trials but seem to have little impact on glycemia in human studies. However, other lipids produced by ruminants, including polar lipids, odd-chain, trans-, and branched-chain fatty acids, produce neutral or contradictory effects on glucose metabolism. Bioactive peptides derived from whey and casein may exert their effects both directly through their insulinotropic effects or renin-angiotensin-aldosterone system inhibition and indirectly by the regulation of incretin hormones. Overall, the results bolster many observational studies in humans and suggest that cow's milk intake reduces the risk of, and can perhaps be used in treating, metabolic disorders. However, the mechanisms of action for most bioactive compounds in milk are still largely undiscovered.

The increased incidence of obesity, which become a global health problem, requires more functional food products with minor side and excellent effects. Calebin A (CbA) is a non-curcuminoid compound, which is reported to be an effective treatment for lipid metabolism and thermogenesis. However, its ability and mechanism of action in improving obesity-associated hyperglycemia remain unclear. This study was designed to explore the effect and mechanism of CbA in hyperglycemia via improvement of inflammation and glucose metabolism in the adipose tissue and liver in high-fat diet (HFD)-fed mice. After 10 weeks fed HFD, obese mice supplemented with CbA (25 and 100 mg/kg) for another 10 weeks showed a remarkable reducing adiposity and blood glucose. CbA modulated M1/M2 macrophage polarization, ameliorated inflammatory cytokines, and restored adiponectin as well as Glut 4 expression in the adipose tissue. In the in vitro study, CbA attenuated pro-inflammatory markers while upregulated anti-inflammatory IL-10 in LPS + IFNγ-generated M1 phenotype macrophages. In the liver, CbA attenuated steatosis, inflammatory infiltration, and protein levels of inflammatory TNF-α and IL-6. Moreover, CbA markedly upregulated Adiponectin receptor 1, AMPK, and insulin downstream Akt signaling to improve glycogen content and increase Glut2 protein. These findings indicated that CbA may be a novel therapeutic approach to treat obesity and hyperglycemia phenotype targeting on adipose inflammation and hepatic insulin signaling.

Obesity has a multifactorial etiology and is known to be a state of chronic low-grade inflammation, known as meta-inflammation. This state is associated with the development of metabolic disorders such as glucose intolerance and nonalcoholic fatty liver disease. Pyruvate is a glycolytic metabolite and a crucial node in various metabolic pathways. However, its role and molecular mechanism in obesity and associated complications are obscure. In this study, we reported that pyruvate substantially inhibited adipogenic differentiation in vitro and its administration significantly prevented HFD-induced weight gain, white adipose tissue inflammation, and metabolic dysregulation. To identify the target proteins of pyruvate, drug affinity responsive target stability was employed with proteomics, cellular thermal shift assay, and isothermal drug response to detect the interactions between pyruvate and its molecular targets. Consequently, we identified cytosolic phospholipase A2 (cPLA2) as a novel molecular target of pyruvate and demonstrated that pyruvate restrained diet-induced obesity, white adipose tissue inflammation, and hepatic steatosis in a cPLA2-dependent manner. Studies with global ablation of cPLA2 in mice showed that the protective effects of pyruvate were largely abrogated, confirming the importance of pyruvate/cPLA2 interaction in pyruvate attenuation of inflammation and obesity. Overall, our study not only establishes pyruvate as an antagonist of cPLA2 signaling and a potential therapeutic option for obesity but it also sheds light on the mechanism of its action. Pyruvate's prior clinical use indicates that it can be considered a safe and viable alternative for obesity, whether consumed as a dietary supplement or as part of a regular diet.

B cell-activating factor (BAFF) is a critical TNF-family cytokine that regulates homeostasis and peripheral tolerance of B2 cells. BAFF overproduction promotes autoantibody generation and autoimmune diseases. During obesity, BAFF is predominantly produced by white adipose tissue (WAT), and IgG autoantibodies against adipocytes are identified in the WAT of obese humans. However, it remains to be determined if the autoantibodies formed during obesity affect WAT remodeling and systemic insulin resistance. Here, we show that IgG autoantibodies are generated in high-fat diet (HFD)-induced obese mice that bind to apoptotic adipocytes and promote their phagocytosis by macrophages. Next, using murine models of obesity in which the gonadal WAT undergoes remodeling, we found that BAFF neutralization depleted IgG autoantibodies, increased the number of dead adipocytes, and exacerbated WAT inflammation and insulin resistance. RNA sequencing of the stromal vascular fraction from the WAT revealed decreased expression of immunoglobulin light-chain and heavy-chain variable genes suggesting a decreased repertoire of B cells after BAFF neutralization. Further, the B cell activation and the phagocytosis pathways were impaired in the WAT of BAFF-neutralized mice. In vitro, plasma IgG fractions from BAFF-neutralized mice reduced the phagocytic clearance of apoptotic adipocytes. Altogether, our study suggests that IgG autoantibodies developed during obesity, at least in part, dampens exacerbated WAT inflammation and systemic insulin resistance.

Adipose tissue, aside from adipocytes, comprises various abundant immune cells. The accumulation of low-grade chronic inflammation in adipose tissue serves as a primary cause and hallmark of insulin resistance. In this study, we investigate the physiological roles of FADD in adipose tissue inflammation, adipogenesis, and adipocyte survival. High levels of Fadd mRNA were observed in mitochondrial-rich organs, particularly brown adipose tissue. To explore its metabolic functions, we generated global Fadd knockout mice, resulting in embryonic lethality, while heterozygous knockout (Fadd+/-) mice did not show any significant changes in body weight or composition. However, Fadd+/- mice exhibited reduced respiratory exchange ratio (RER) and serum cholesterol levels, along with heightened global and adipose inflammatory responses. Furthermore, AT masses and expression levels of adipogenic and lipogenic genes were decreased in Fadd+/- mice. In cellular studies, Fadd inhibition disrupted adipogenic differentiation and suppressed the expression of adipogenic and lipogenic genes in cultured adipocytes. Additionally, Fadd overexpression caused adipocyte death in vitro with decreased RIPK1 and RIPK3 expression, while Fadd inhibition downregulated RIPK3 in iWAT in vivo. These findings collectively underscore the indispensable role of FADD in adipose inflammation, adipogenesis, and adipocyte survival.

Obesity is an important condition affecting the quality of life of numerous patients and increasing their associated risk for multiple diseases, including tumors and immune-mediated disorders. Inflammation appears to play a major role in the development of obesity and represents a central point for the activity of cellular and humoral components in the adipose tissue. Macrophages play a key role as the main cellular component of the adipose tissue regulating the chronic inflammation and modulating the secretion and differentiation of various pro- and anti-inflammatory cytokines. Inflammation also involves a series of signaling pathways that might represent the focus for new therapies and interventions. Weight loss is essential in decreasing cardiometabolic risks and the degree of associated inflammation; however, the latter can persist for long after the excess weight is lost, and can involve changes in macrophage phenotypes that can ensure the metabolic adjustment. A clear understanding of the pathophysiological processes in the adipose tissue and the interplay between obesity and chronic inflammation can lead to a better understanding of the development of comorbidities and may ensure future targets for the treatment of obesity.

Obesity is closely associated with lipid accumulation, inflammation and intestinal microbiota dysbiosis. Short- and long-chain type structured lipids (SLCTs) are kinds of low-calorie structured lipids and demonstrate anti-obesity and hypolipidemia bioactivity. The objective of this study is to investigate the potential effects of dietary supplementation of SLCTs rich in short-chain fatty acids and polyunsaturated fatty acids on high-fat-diet-induced obesity and gut microbiota modulation in C57BL/6J mice.

Results showed that SLCTs supplementation ameliorated body weight, dyslipidemia, liver lipid accumulation, liver injury and systemic inflammation in obese mice. As expected, immunohistochemical analysis showed that SLCTs significantly increased the expression of proliferator-activated receptor alpha and decreased the expression of Toll-like receptor 4 in liver tissue. Furthermore, SLCTs supplementation significantly downregulated the expression level of liver inflammation-related genes while upregulating the expression level of liver lipid metabolism-related genes. Additionally, SLCTs supplementation markedly enhanced the diversity of gut microbiota, reduced the Firmicutes/Bacteroidetes ratio and increased the diversity and richness of beneficial intestinal microorganisms, such as Bacteroides, Lactobacillus, Lachnospiraceae NK4A136 group, Alloprevotella and Ruminococcaceae UCG-014.

Our work suggested that SLCTs may have the potential to reduce obesity associated with a high-fat diet by regulating liver metabolism, inflammation and gut microbiota. © 2024 Society of Chemical Industry.

Obesity is characterized by adipose tissue expansion, extracellular matrix remodelling and unresolved inflammation that contribute to insulin resistance and fibrosis. Adipose tissue macrophages represent the most abundant class of immune cells in adipose tissue inflammation and could be key mediators of adipocyte dysfunction and fibrosis in obesity. Although macrophage activation states are classically defined by the M1/M2 polarization nomenclature, novel studies have revealed a more complex range of macrophage phenotypes in response to external condition or the surrounding microenvironment. Here, we discuss the plasticity of adipose tissue macrophages (ATMs) in response to their microenvironment in obesity, with special focus on macrophage infiltration and polarization, and their contribution to adipose tissue fibrosis. A better understanding of the role of ATMs as regulators of adipose tissue remodelling may provide novel therapeutic strategies against obesity and associated metabolic diseases.

The findings from previous epidemiological studies of the association between regional body fat and depressive symptoms have been unclear. We aimed to determine the association between the body fat in different regions and depressive symptoms based on data from the National Health and Nutrition Examination Survey (NHANES).

This study included 3393 participants aged ≥ 20 years from the NHANES performed during 2011-2018. Depressive symptoms were assessed using the Patient Health Questionnaire-9. The fat mass (FM) was measured in different regions using dual-energy X-ray absorptiometry to determine the total FM, trunk FM, arm FM, and leg FM. The FM index (FMI) was obtained by dividing the FM in kilograms by the square of the body height in meters. Weighted data were calculated in accordance with analytical guidelines. Linear logistic regression models were used to quantify the association between regional FMI and depressive symptoms. Univariate and stratified analyses were also performed.

The participants in this study comprised 2066 males and 1327 females. There were 404 (11.91%) participants with depressive symptoms, who were aged 40.89 ± 11.74 years and had a body mass index of 30.07 ± 7.82 kg/m². A significant association was found between total FMI and depressive symptoms. In the fully adjusted multivariate regression model, a higher total FMI (odds ratio = 2.18, 95% confidence interval [CI] = 1.08-4.39) was related to a higher risk of depressive symptoms, while increased total FMI (β = 1.55, 95% CI = 0.65-2.44, p = 0.001), trunk FMI (β = 0.57, 95% CI = 0.04-1.10, p = 0.036), and arm FMI (β = 0.96, 95% CI = 0.33-1.59, p = 0.004) were significantly associated with PHQ-9 (Patient Health Questionnaire-9) scores, whereas the leg FMI was not (p = 0.102). The weighted association between total FMI and depressive symptoms did not differ significantly between most of the subpopulations (all p values for interaction > 0.05). The risk of having depression was higher in individuals who were non-Hispanic Whites, smokers, drinkers, obese, and had diabetes and thyroid problems (p < 0.05).

These findings suggest that the population with a higher regional FMI is more likely to have depressive symptoms, especially in those who also have an increased total FMI. The association is more pronounced in individuals who are smokers, drinkers, obese, and have diabetes and thyroid problems.

Acne vulgaris is one of the most common skin diseases. The current understanding of acne primarily revolves around inflammatory responses, sebum metabolism disorders, aberrant hormone and receptor expression, colonization by Cutibacterium acnes, and abnormal keratinization of follicular sebaceous glands. Although the precise mechanism of action remains incompletely understood, it is plausible that macrophages exert an influence on these pathological features. Macrophages, as a constituent of the human innate immune system, typically manifest distinct phenotypes across various diseases. It has been observed that the polarization of macrophages toward the M1 phenotype plays a pivotal role in the pathogenesis of acne. In recent years, extensive research on acne has revealed an increasing number of natural remedies exhibiting therapeutic efficacy through the modulation of macrophage polarization. This review investigates the role of cutaneous macrophages, elucidates their potential significance in the pathogenesis of acne, a prevalent chronic inflammatory skin disorder, and explores the therapeutic mechanisms of natural plant products targeting macrophages. Despite these insights, the precise role of macrophages in the pathogenesis of acne remains poorly elucidated. Subsequent investigations in this domain will further illuminate the pathogenesis of acne and potentially offer guidance for identifying novel therapeutic targets for this condition.

Eosinophils are a type of granulocyte named after the presence of their eosin-stained granules. Traditionally, eosinophils have been best known to play prominent roles in anti-parasitic responses and mediating allergic reactions. Knowledge of their behaviour has expanded with time, and they are now recognized to play integral parts in the homeostasis of gastrointestinal, respiratory, skeletal muscle, adipose, and connective tissue systems. As such, they are implicated in a myriad of pathologies, and have been the target of several medical therapies. This review focuses on the lifespan of eosinophils, from their origins in the bone marrow, to their tissue-resident role. In particular, we wish to highlight the functions of eosinophils in non-mucosal tissues with skeletal muscle and the adipose tissues as examples, and to discuss the current understanding of their participation in diseased states in these tissues.

Obesity is epidemic and of great concern because of its comorbid and costly inflammatory-driven complications. Extensive investigations in mice have elucidated highly coordinated, well-balanced interactions between adipocytes and immune cells in adipose tissue that maintain normal systemic metabolism in the lean state, while in obesity, proinflammatory changes occur in nearly all adipose tissue immune cells. Many of these changes are instigated by adipocytes. However, less is known about obesity-induced adipose-tissue immune cell alterations in humans. Upon high-fat diet feeding, the adipocyte changes its well-known function as a metabolic cell to assume the role of an immune cell, orchestrating proinflammatory changes that escalate inflammation and progress during obesity. This transformation is particularly prominent in humans. In this review, we (a) highlight a leading and early role for adipocytes in promulgating inflammation, (b) discuss immune cell changes and the time course of these changes (comparing humans and mice when possible), and (c) note how reversing proinflammatory changes in most types of immune cells, including adipocytes, rescues adipose tissue from inflammation and obese mice from insulin resistance.

Several P2Y nucleotide receptors have been shown to be involved in the early stage of adipocyte differentiation in vitro and insulin resistance in obese mice; however, the exact receptor subtype(s) and its underlying molecular mechanism in relevant human cells are unclear. Here, using human primary visceral preadipocytes as a model, we found that during preadipocyte-to-mature adipocyte differentiation, the P2Y2 nucleotide receptor (P2Y2R) was the most upregulated subtype among the eight known P2Y receptors and the only one further dramatically upregulated after inflammatory TNFα treatment. Functional studies indicated that the P2Y2R induced intracellular Ca2+, ERK1/2, and JNK signaling but not the p38 pathway. In addition, stimulation of the P2Y2R suppressed basal and insulin-induced phosphorylation of AKT, accompanied by decreased GLUT4 membrane translocation and glucose uptake in mature adipocytes, suggesting a role of P2Y2R in insulin resistance. Mechanistically, we found that activation of P2Y2R did not increase lipolysis but suppressed PIP3 generation. Interestingly, activation of P2Y2R triggered Gi-protein coupling, and pertussis toxin pretreatment largely inhibited P2Y2R-mediated ERK1/2 signaling and cAMP suppression. Further, treatment of the cells with AR-C 118925XX, a selective P2Y2R antagonist, significantly inhibited adipogenesis, and P2Y2R knockout decreased mouse body weight gain with smaller eWAT mass infiltrated with fewer macrophages as compared to WT mice in response to a Western diet. Thus, we revealed that terminal adipocyte differentiation and inflammation selectively upregulate P2Y2R expression and that P2Y2R mediates insulin resistance by suppressing the AKT signaling pathway, highlighting P2Y2R as a potential new drug target to combat obesity and type-2 diabetes.

Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction have primary importance in obesity. Large quantity of macrophages is accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway promotes more macrophage accumulation into the obese adipose tissue. However, obesity-induced changes in adipose tissue macrophage density are mainly dependent on increases in the triple-positive cluster of differentiation (CD)11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. As epigenetic regulators, microRNAs (miRNAs) are one of the most important mediators of obesity. miRNAs are expressed by adipocytes as well as macrophages and regulate inflammation with the expression of target genes. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-α) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1β) by macrophages; both adipocyte and macrophage induction by toll-like receptor-4 (TLR4) through nuclear factor-kappaB (NF-κB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in mutual message transmission between adipocyte and macrophage and in the development of adipose tissue inflammation. Thus, the metabolic status of adipocytes and their released exosomes are important determinants of macrophage inflammatory output. However, old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. As a single miRNA can be able to regulate a variety of target genes and signaling pathways, reciprocal transfer of miRNAs between adipocytes and macrophages via miRNA-loaded exosomes reorganizes the different stages of obesity. Changes in the expression of circulating miRNAs because of obesity progression or anti-obesity treatment indicate that miRNAs could be used as potential biomarkers. Therefore, it is believed that targeting macrophage-associated miRNAs with anti-obesity miRNA-loaded nano-carriers may be successful in the attenuation of both obesity and adipose tissue inflammation in clinical practice. Moreover, miRNA-containing exosomes and transferable mitochondria between the adipocyte and macrophage are investigated as new therapeutic targets for obesity-related metabolic disorders.

The signals and structure of the tissues in which leukocytes reside critically mould leukocyte function and development and have challenged our fundamental understanding of how to define and categorize tissue-resident immune cells. One specialized tissue niche that has a powerful effect on immune cell function is adipose tissue. The field of adipose tissue leukocyte biology has expanded dramatically and has revealed how tissue niches can shape immune cell function and reshape them in a setting of metabolic stress, such as obesity. Most notably, adipose tissue macrophages and T cells are under intense investigation due to their contributions to adipose tissue in the lean and obese states. Both adipose tissue macrophages and T cells have features associated with the metabolic function of adipose tissue that are distinct from features of macrophages and T cells that are classically characterized in other tissues. This Review provides state-of-the-art understanding of adipose tissue macrophages and T cells and discusses how their unique niche can help us to better understand diversity in leukocyte responses.

Macrophages play critical roles in inflammation and tissue homeostasis, and their functions are regulated by various autocrine, paracrine, and endocrine factors. We have previously shown that CTRP6, a secreted protein of the C1q family, targets both adipocytes and macrophages to promote obesity-linked inflammation. However, the gene programs and signaling pathways directly regulated by CTRP6 in macrophages remain unknown. Here, we combine transcriptomic and phosphoproteomic analyses to show that CTRP6 activates inflammatory gene programs and signaling pathways in mouse bone marrow-derived macrophages (BMDMs). Treatment of BMDMs with CTRP6 upregulated proinflammatory, and suppressed the antiinflammatory, gene expression. We also showed that CTRP6 activates p44/42-MAPK, p38-MAPK, and NF-κB signaling pathways to promote inflammatory cytokine secretion from BMDMs, and that pharmacologic inhibition of these signaling pathways markedly attenuated the effects of CTRP6. Pretreatment of BMDMs with CTRP6 also sensitized and potentiated the BMDMs response to lipopolysaccharide (LPS)-induced inflammatory signaling and cytokine secretion. Consistent with the metabolic phenotype of proinflammatory macrophages, CTRP6 treatment induced a shift toward aerobic glycolysis and lactate production, reduced oxidative metabolism, and elevated mitochondrial reactive oxygen species production in BMDMs. Importantly, in accordance with our in vitro findings, BMDMs from CTRP6-deficient mice were less inflammatory at baseline and showed a marked suppression of LPS-induced inflammatory gene expression and cytokine secretion. Finally, loss of CTRP6 in mice also dampened LPS-induced inflammation and hypothermia. Collectively, our findings suggest that CTRP6 regulates and primes the macrophage response to inflammatory stimuli and thus may have a role in modulating tissue inflammatory tone in different physiological and disease contexts.

Metabolic syndrome (MS) is a growing disorder affecting thousands of people worldwide, especially in industrialised countries, increasing mortality. Oxidative stress, hyperglycaemia, insulin resistance, inflammation, dysbiosis, abdominal obesity, atherogenic dyslipidaemia and hypertension are important factors linked to MS clusters of different pathologies, such as diabesity, cardiovascular diseases and neurological disorders. All biochemical changes observed in MS, such as dysregulation in the glucose and lipid metabolism, immune response, endothelial cell function and intestinal microbiota, promote pathological bridges between metabolic syndrome, diabesity and cardiovascular and neurodegenerative disorders. This review aims to summarise metabolic syndrome's involvement in diabesity and highlight the link between MS and cardiovascular and neurological diseases. A better understanding of MS could promote a novel strategic approach to reduce MS comorbidities.

Obesity is associated with chronic low-grade white adipose tissue (WAT) inflammation that can contribute to the development of insulin resistance in mammals. Previous studies have identified interleukin (IL)-12 as a critical upstream regulator of WAT inflammation and metabolic dysfunction during obesity. However, the cell types and mechanisms that initiate WAT IL-12 production remain unclear. Here we show that conventional type 1 dendritic cells (cDC1s) are the cellular source of WAT IL-12 during obesity through analysis of mouse and human WAT single-cell transcriptomic datasets, IL-12 reporter mice and IL-12p70 protein levels by enzyme-linked immunosorbent assay. We demonstrate that cDC1s contribute to obesity-associated inflammation by increasing group 1 innate lymphocyte interferon-γ production and inflammatory macrophage accumulation. Inducible depletion of cDC1s increased WAT insulin sensitivity and systemic glucose tolerance during diet-induced obesity. Mechanistically, endocytosis of apoptotic bodies containing self-DNA by WAT cDC1s drives stimulator of interferon genes (STING)-dependent IL-12 production. Together, these results suggest that WAT cDC1s act as critical regulators of adipose tissue inflammation and metabolic dysfunction during obesity.