Macrophages are at the critical interface of immunity and metabolism. Metabolic reprogramming of macrophages, also known as meta-inflammation, has major implications in the pathogenesis of many chronic diseases. The infiltration and polarization of macrophages play critical roles in tissue homeostasis and inflammatory responses, thereby reshaping the tissue microenvironment. Macrophages have unique phenotypical and functional plasticity, making them attractive as therapeutic targets. Nutrient-sensing ghrelin is a gastrointestinal peptide hormone that functions through its receptor, growth hormone secretagogue receptor (GHSR), and is known to trigger hunger sensation, stimulate food intake, and promote fat deposition. Emerging evidence indicates that ghrelin/GHSR signaling is also a critical regulator of immunometabolism, modulating metabolic pathways in macrophages to enable their adaptation and functional responses to the tissue microenvironment. Here, we highlight the regulatory mechanisms of the ghrelin/GHSR system in macrophage reprogramming in meta-inflammation. In particular, we demonstrate the infiltration and differentiation of tissue-resident macrophages, and their functional impacts on the development and progression of metabolic and inflammatory dysfunctions. The dynamic and multifaceted roles of ghrelin/GHSR signaling in macrophage reprogramming could be leveraged to develop novel immunotherapies for meta-inflammatory conditions and diseases.
Monoacylglycerol (MAG) is an important bioactive lipid metabolite/intermediate, playing crucial roles in energy homeostasis and cellular signaling. This review explores MAG's chemical structure, classification, and metabolic pathways. We also discuss the emerging evidence for MAG as a signaling molecule, with particular emphasis on their interactions with cannabinoid receptor 1 and cannabinoid receptor 2 and G-protein-coupled receptor 119. We focus on examining the diverse and tissue-specific functions of MAG in the context of metabolic diseases, including the roles of MAG in nutrient absorption, appetite regulation, obesity, glucose homeostasis, and lipid metabolism. Furthermore, we address therapeutic approaches in modulating MAG metabolism and challenges in development, considering the complexity of targeting peripheral tissues. This review provides insights into the multifaceted roles of MAG in metabolic health and disease, paving the way for novel therapeutic strategies in the management of metabolic disorders.
Background:The economic and medical burden of sepsis worldwide underscores the need for novel therapeutics. Early sepsis involves dramatic metabolic changes. Classically activated macrophages, stimulated with lipopolysaccharide and interferon-γ, shift their metabolism to glycolysis. The reactive glycolytic metabolite, methylglyoxal, accumulates and has been associated with adverse outcomes in sepsis. We previously demonstrated that hypoxia-inducing factor-1α (HIF-1α) contributes to methylglyoxal accumulation. Treatment with lipopolysaccharide or interferon-γ individually stabilized HIF-1α protein; however, co-stimulation with both lipopolysaccharide and interferon-γ accelerated HIF-1α stabilization, implying a shared upstream mediator. Therefore, we sought to characterize mechanisms underlying methylglyoxal accumulation. Methods:Quantitative polymerase chain reaction and immunoblotting were used to analyze HIF-1α expression in classically activated primary mouse macrophages. Results:Nos2 expression was induced by lipopolysaccharide or interferon-γ and markedly enhanced by combined treatment, possibly linking inducible nitric oxide synthase (iNOS) activity to HIF-1α stabilization. Inhibiting iNOS with l-NG-Nitro arginine methyl ester (l-NAME) reduced HIF-1α stabilization in a dose-dependent manner. Mitochondrial reactive oxygen species (mROS), generated following nitric oxide inhibition of cytochrome oxidase, similarly contributed to HIF-1α stabilization, as shown by the effects of suppressors of ROS production by mitochondrial complex I (S1QEL1.1) and III (S3QEL1.2) and the compartment-specific antioxidant Mito-TEMPO. Blocking mROS also decreased Il1b, Il6, and Cxcl10 expression in activated macrophages, supporting a broader impact on inflammation. Additionally, S1QEL1.1 treatment reduced accumulation of methylglyoxal. Conclusions:These data support a model in which nitric oxide-mediated mitochondrial dysfunction increases mROS, promoting HIF-1α stabilization and methylglyoxal accumulation, thereby shaping macrophage inflammatory responses. Thus, targeting mROS may offer a therapeutic strategy to improve sepsis outcomes.
This viewpoint focuses on core evidence regarding the cross-talk between adipose tissue inflammation and hepatic inflammation that possibly leads to the progression of metabolic dysfunction-associated steatotic liver disease to metabolic dysfunction-associated steatohepatitis, hepatic fibrosis, and cirrhosis. It is highlighted that the adipose tissue and hepatic inflammation increase in parallel with insulin resistance, possibly affecting each other, thereby leading to advanced liver disease. This interplay is partly mediated via adipokines produced by the adipose tissue, hepatokines produced by the liver, and cytokines produced by the immune cells infiltrating both the adipose tissue and the liver.
Background:T-cell fate and function are profoundly shaped by microenvironmental nutrient availability. The branched-chain amino acid, leucine, is essential for T-cell function, with its uptake via the solute carrier family 7-member 5 transporter increasing upon activation. As the enzyme catalyzing the first step of leucine degradation, the cytosolic branched-chain aminotransferase (BCATc) is induced upon T-cell activation and subsequently acts as a negative regulator of T-cell activity. However, a major knowledge gap remains regarding how BCATc modulates T-cell function beyond activation, specifically within differentiated T helper cells. Methods:Novel T-cell conditional knockout mouse models of BCATc, and its mitochondrial isoenzyme, BCATm, were characterized and used as a source of in vitro or ovalbumin-induced CD4+ T-cell subsets in the presence of the leucine competitive antagonist, N-acetyl leucine amide (NALA). The studies were complemented by transcriptomic analysis of human T cells using the genomic platform R2. Results:Loss of BCATc enhanced TH1 phenotype as evidenced by the increased expression of T-bet and interferon-γ. Leucine, but not the BCAT isoenzymes, was critical for TH2 and TH17 function as evidenced by the severe reduction in interleukin [IL]-13 and IL-17 release in the presence of NALA. Lastly, a loss of BCATc, or its mitochondrial isozyme, BCATm, facilitated a shift of regulatory T cells (Tregs) to a TH1-like phenotype as judged by the increased populations of T-bet+Foxp3+Tregs. Conclusions:BCATc is the dominant BCAT isoenzyme with immunoregulatory function in CD4+ T-cell subsets and targetable potential in T-cell immunity.
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a leading cause of hepatocellular carcinoma (HCC), driven in part by oxidative stress-induced immune dysfunction that limits the efficacy of immunotherapy. In a recent study, Yu et al developed a vitamin E-incorporated lipid nanoparticle designed to enhance hepatocyte‑specific mRNA delivery while simultaneously buffering oxidative stress in the hepatic microenvironment. By restoring the activity of the redox‑sensitive phosphatase T‑cell protein tyrosine phosphatase and suppressing signal transducer and activator of transcription (STAT) signaling, this strategy improves metabolic homeostasis, reduces inflammatory signaling, and enhances responsiveness to immune checkpoint blockade. These findings illustrate how rational nanoparticle engineering can integrate therapeutic delivery with microenvironmental reprogramming in chronic metabolic disease.
Obesity during pregnancy not only affects maternal health but also puts offspring at high risk of obesity and of metabolic and cardiovascular diseases later in life, often regardless of their own lifestyle choices. This process, known as developmental programming, is increasingly being recognized as a critical factor shaping long-term health outcomes. In addition, a growing body of research highlights the importance of immunometabolism, the metabolism of immune cells, in the pathogenesis of obesity, metabolic disorders, cardiovascular disease, and cancer. Although the effects of maternal obesity on offspring health have been well documented in both epidemiological studies and preclinical models, its influence on the developing immune system and immunometabolic pathways is only beginning to be revealed. In this review, we explore the metabolic and inflammatory dimensions of developmental programming and discuss how an adverse maternal environment may shape the offspring's immunometabolic landscape.
Specialized pro-resolving mediators (SPMs) derived from docosahexaenoic acid (DHA), particularly D-series resolvins (RvD1, RvD2, RvD3, and RvD5), function to terminate inflammation while preserving host defense. They are synthesized from DHA by lipoxygenases and act through G‑protein‑coupled receptors and lipid‑sensing transcription factors (TFs). These mediators reprogram macrophage metabolism towards fatty‑acid oxidation and oxidative phosphorylation, accelerate efferocytosis, and promote tissue repair. Here, we synthesize current knowledge on their biosynthesis, receptor signaling, and immunometabolic rewiring within macrophages, and critically appraise their therapeutic potential across cardiometabolic, musculoskeletal, autoimmune, and ischemia/reperfusion disorders. We also discuss analytical controversies surrounding their in vivo low‑abundance detection, and outline translational challenges including short half‑life, formulation stability, and emerging synthetic agonists. Finally, we propose priority research directions, from single-cell spatial lipidomics to clinical translation, to define the next frontier for resolvin-based immunotherapies.
Background:Severe coronavirus disease 2019 (COVID-19) is characterized by a hyperinflammatory state associated with an exacerbated inflammatory activation of monocytes and macrophages in the respiratory tract. Metformin has been identified as a potent monocyte inflammatory suppressor, and it has been demonstrated to attenuate inflammation in COVID-19. The mechanisms underlying metformin's anti-inflammatory effects are, however, unclear. We thus sought to investigate metformin's main interactions and their respective isolated effects in modulating monocyte inflammatory response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) stimulation.Methods:Classical human monocytes were isolated from healthy 18 to 40-year-old individuals and stimulated in vitro with recombinant spike protein subunit 1 (rS1) to assess glycolytic and oxidative metabolic responses by Seahorse extracellular flux analysis and inflammatory gene expression by quantitative polymerase chain reaction. Stimulated monocytes were either pretreated with metformin, rotenone, S1QEL, or A769662.Results:Monocytes stimulated in vitro with rS1 showed an increased glycolytic response associated with production of pro-inflammatory cytokines. Metformin pretreatment reduced glycolytic activation while partially suppressing inflammation. Rotenone-dependent mitochondrial complex I inhibition was not able to replicate the same effect, and neither was complex I-specific reactive oxygen species scavenging. Conversely, A769662-induced AMP-activated protein kinase (AMPK) activation led to suppressed glycolytic inflammatory response and cytokine expression pattern similar to metformin, thus suggesting AMPK modulation as a possible central component for metformin's mode of action upon S1 stimulation.Conclusions:In summary, further investigation into the interactions underlying AMPK activity on monocytes in the context of SARS-CoV-2 may provide a better elucidation of metformin's anti-inflammatory effect.
Background:Temperature, as seen during fever, plays a pivotal role in modulating immune responses and maintaining cellular homeostasis. Shifts in temperature influence the thermodynamic feasibility of metabolic reactions, with Gibbs free energy (ΔG) serving as a key indicator of the spontaneity of reactions under specific conditions. By altering ΔG in response to temperature changes across various metabolite concentrations and cell types, we can gain insights into the thermodynamic properties of metabolic pathways and identify critical factors involved in metabolism and immune function. Using Max-min Driving Force (MDF) analysis, we can assess changes in ΔG by varying temperature and metabolite concentrations, allowing for a detailed examination of thermodynamic feasibility at both the pathway and individual reaction levels. Method:Minimum driving force analysis was conducted to estimate the thermodynamic feasibility of metabolic pathways, including glycolysis, gluconeogenesis, oxidative phosphorylation, the pentose phosphate pathway, the tricarboxylic acid cycle, arginine and proline metabolism, amino sugar and nucleotide sugar metabolism (collectively referred to as amino sugar metabolism), leukotriene metabolism, and other amino acid pathways. The analysis was performed across a temperature range of 310.15 to 314.15 K. In addition, the ΔG for each reaction was calculated using standard Gibbs free energy values obtained from the equilibrator. Results:In this study, MDF analysis is applied to measure the changes in the driving force of pathways and the ΔG of each reaction at normal human core temperature (310.15 K) and elevated temperatures (up to 314.15 K). Additionally, we explore how shifts in the thermodynamic feasibility of reactions under immune activation, compared with normal physiological conditions, highlight key metabolic intermediates, such as fructose-1,6-bisphosphate, glucose-6-phosphate, and several steps in glutamate utilization, as important regulators of metabolic processes and immune responses. Conclusion:In conclusion, this study demonstrates that MDF-based thermodynamic analysis effectively captures temperature-dependent shifts in metabolic pathway feasibility and highlights glutamate metabolism as a key regulator of immune function. These findings underscore the utility of thermodynamic frameworks in advancing system-level understanding of human metabolism and immune regulation.
Cellular metabolism is crucial for energy production, which regulates cell function and survival. In recent years, the importance of metabolism in modulating immune cell proliferation, differentiation, and function has become a prominent area of research. However, little is still known about the metabolic regulation of B cell function and humoral immunity, both in healthy individuals as well as in those with various conditions and diseases. In this viewpoint, we will discuss the current understanding of immunometabolic regulation of humoral responses in aging people living with HIV, and in people without HIV. We propose the possibility to target metabolic molecules and pathways to prevent the negative effects of aging and HIV and progress towards an overall better immune system, not only in individuals with HIV but also in those living with other inflammatory conditions and diseases.
Background:Immunometabolism has emerged as a flourishing field exploring how cellular metabolism regulates immune responses. Peripheral blood mononuclear cells (PBMCs) have so far been the primary sample type used for immunometabolic profiling. However, PBMCs isolation requires large blood volumes, can pose logistic challenges, and requires specialized skills for processing. Thus, using whole blood (WB) samples, which are less technically challenging to process, could serve as a viable alternative for metabolic characterization of circulating immune cell populations. Yet, how well WB immunometabolic profiles match those from PBMCs remains unknown. Therefore, we aimed to compare the immunometabolic profile of WB with that of PBMCs. Method:Paired WB and PBMCs samples were collected from six healthy donors. WB was collected in CryoStor®-CS10 medium, while PBMCs were isolated using Ficoll density gradient. Using spectral flow cytometry, we identified immune cell populations and assessed their metabolic states. Results:Our findings show an overall high similarity in the immune cell subset frequencies between WB and PBMCs as well as their metabolic profiles. However, differences in the expression of certain metabolic markers were noted in some immune populations. Specifically, glucose transporter 1 levels were higher in CD8+ TEMRA, NKT, and NK cells from PBMCs, while ATP5a levels were higher in naïve CD4+ T cells from WB. Conclusions:These results suggest that WB can be an alternative to PBMCs for metabolic profiling of immune cells. Nevertheless, for some specific cell subsets, caution should be taken when comparing immunometabolic data between WB and PBMCs.
Most chronic diseases including coronary heart disease, obesity, diabetes, cancer, and multiple neurodegenerative diseases are driven by dysregulated lipid metabolism. In fact, many common drugs taken by millions including aspirin, statins, fibrates, and others improve health by reorganizing systemic lipid metabolism. Although we have a wealth of information on the enzymes and pathways maintaining lipid metabolic homeostasis in our human cells, there is much less known in regard to how our gut microbiome may coordinate with the host to control systemic lipid metabolism. With advances in untargeted metabolomics, there is a rapidly expanding list of gut microbe-derived lipid metabolites with unannotated function. Many of these bacterial lipids can be assimilated into host lipids and alter host lipid metabolic processes. Here, we discuss how gut microbe-derived lipids may be further metabolized by the host through metaorganismal metabolic pathways. We also discuss the untapped therapeutic potential for targeting metaorganismal lipid metabolism for the improvement of human health.
Background:Chronic low-grade inflammation in adipose tissue, primarily driven by macrophages, plays a central role in obesity pathophysiology. C1q/TNF-related protein 6 (CTRP6), a member of the CTRP family, has emerged as a key regulator of this inflammatory process. Here, we demonstrate that CTRP6 expression is upregulated in adipose tissue macrophages during obesity, where it acts as a potent modulator of macrophage polarization by suppressing M2 polarization. Methods:In RAW264.7 macrophages, we distinguished M1 and M2 polarization, induced by lipopolysaccharide (LPS) + interferon-gamma (IFNγ) and interleukin (IL)-4, respectively, by selecting two marker genes for each polarization type from a set of five widely used markers, based on a time-course analysis. We then assessed the effects of recombinant CTRP6 protein treatment on M1 and M2 polarization. Finally, we validated our findings in primary bone marrow-derived macrophages (BMDMs). Results:In naïve RAW264.7 macrophages, recombinant CTRP6 protein upregulated M1 marker genes (Tnf, Nos2) while downregulating M2 markers (Mrc1, Pparg). During M1 polarization induced by LPS+IFNγ, CTRP6 treatment had no significant effect. However, during IL-4-induced M2 polarization, CTRP6 not only enhanced M1 markers but also strongly suppressed M2 markers by inhibiting anti-inflammatory signal transducer and activator of transcription 6 (STAT6) signaling and relieving the inhibition of pro-inflammatory ERK1/2 signaling. Additionally, CTRP6 impaired mitochondrial activity, favoring glycolysis in macrophages. Importantly, these effects were serum-independent and confirmed in BMDMs. Conclusions:Since endogenous CTRP6 expression in BMDMs is upregulated by M1 polarization inducers, it may further hinder inflammation resolution, even in the presence of IL-4 during tissue repair, establishing it as a key driver of adipose tissue inflammation in obesity.
The discovery of itaconate as an immunoregulatory metabolite has transformed the field of immunometabolism and opened multiple therapeutic avenues over the past decade. While the immunological functions of itaconic acid have been extensively studied, several aspects of its biochemistry-particularly in vivo utilization pathways-have remained unclear. In a recent study published in Nature Metabolism, Willenbockel et al apply carbon tracing to uncover the metabolic fate of itaconate within the organism. Insights from this work have important implications for understanding the physiological roles of itaconate and for advancing itaconate-based therapeutic strategies.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID are complex, disabling conditions that have emerged as significant public health challenges, affecting millions worldwide. Despite their growing prevalence, effective diagnostics and treatments remain limited, largely due to an incomplete understanding of their underlying pathophysiology. Both conditions share hallmark symptoms of chronic fatigue, cognitive dysfunction, and postexertional malaise, but their biological underpinnings remain to be elucidated. Neuroimaging offers a promising, noninvasive window into the brain's metabolic landscape and has the potential to uncover objective biomarkers for these conditions. In this mini review, we highlight recent advancements in metabolic neuroimaging, particularly positron emission tomography and magnetic resonance imaging/magnetic resonance spectroscopy, that reveal alterations in glucose and oxygen metabolism, neurotransmitter balance, and oxidative stress. These insights point toward shared disruptions in brain energy metabolism and neuroinflammatory processes, which may underlie the persistent symptoms in both ME/CFS and Long-COVID. Importantly, while some findings overlap, inconsistencies in metabolite profiles between ME/CFS and Long-COVID underscore the need for further stratification and longitudinal research. Standardizing definitions, such as identifying Long-COVID patients who meet ME/CFS diagnostic criteria, could help improve study comparability. By summarizing current imaging evidence, this review underscores the potential of neuroimaging to identify imaging biomarkers to advance the clinical diagnosis of Long-COVID and identify therapeutic targets for treatment development. As we continue to face the growing burden of Long-COVID and ME/CFS, metabolic imaging may serve as a powerful tool to bridge gaps in knowledge and accelerate progress toward effective care.
Macrophages play a crucial role in the innate immune system. They are present in most tissues, where they contribute to maintain homeostasis. Kupffer cells have specialized immunometabolic functions that link immune regulation and metabolic homeostasis directly. This enables them to regulate hepatic metabolism by controlling lipid handling and inflammatory responses. Consequently, there is growing interest in developing strategies to selectively modulate the function, polarity, distribution, behavior, and phenotype of Kupffer cells depending on the pathophysiological context. Given their plasticity and contribution to metabolic dysfunction-associated steatotic liver disease (MASLD), it is of increasing interest to find strategies that can selectively modulate Kupffer cell's plasticity to control their distribution and phenotype depending on the pathophysiological context. This would modify their interaction with other cells in the liver niche, particularly hepatocytes, in the context of both atherosclerosis and MASLD. Future perspectives should focus on understanding how changes in the uptake capacity of Kupffer cells occur under conditions of lipid overload, and on exploring paracrine signals within the liver that can modulate their activation using advanced techniques such as high resolution spatial liver profiling.
In a recent Nature publication, Lesbats et al uncover the molecular fate of phagocytosed bacterial contents. The authors observed incorporation of bacterial biomolecules (amino acids, metabolites) into those of the host macrophage through stable isotope labeling and mass spectrometry. Further, the authors found that the state of the phagocytosed bacteria, living or dead, dramatically alters the macrophage's metabolic program toward either a pro-inflammatory or a "recycling" direction, respectively. This commentary summarizes these findings and further discusses the implications of this work in a broader sense.
The intricate interplay between cellular metabolism and immune function has emerged as a pivotal area of research in immunology. Macrophages, as central players in the innate immune system, exhibit remarkable metabolic flexibility that influences their activation states and functional outputs, with important implications for the pathophysiology of inflammatory diseases and cancer. A recent study by Zotta and colleagues provides new insights into the role of mitochondrial complex III (CIII) in regulating the anti-inflammatory cytokine interleukin-10 (IL-10) and its implications for tumor immunity.
A significant barrier to the success of adoptive cell therapies (ACTs) in cancer treatment is the inadequate persistence of T-cells following infusion. In vitro T-cell expansion is a crucial component of ACTs; therefore, preconditioning during culture may enhance their in vivo survival and therapeutic efficacy. Here, we discuss a recent article by Greg Delgoffe and colleagues that was published in Cell Metabolism in April 2025, providing evidence that pharmacologic metabolic rewiring of activated T-cells during in vitro expansion enhances their engraftment postinfusion and improves cellular immunotherapies.
