The Evolving Role of Macrophage Metabolic Reprogramming in Obesity.

Recent research has extensively explored the critical role of energy metabolism in shaping the inflammatory response and polarization of macrophages in obesity. This rapidly growing field emphasizes the need to understand the connection between metabolic processes that support macrophage polarization in obesity. While most published research in this area has focused on glucose and fatty acids, how the flux through other metabolic pathways (such as ketone and amino acid oxidation) in macrophages is altered in obesity is not well defined. This review summarizes the main alterations in uptake, storage, and oxidation of oxidative substrates (glucose, fatty acids, ketone bodies and amino acids) in macrophages and how these alterations are linked to macrophage polarization and contribution to augmented inflammatory markers in obesity. The review also discusses how oxidative substrates could modulate macrophage energy metabolism and inflammatory responses via feeding into other non-oxidative pathways (such as the pentose phosphate pathway, triacylglycerol synthesis/accumulation), via acting as signalling molecules, or via mediating post-translational modifications (such as O-GlcNAcylation or β-hydroxybutyrylation). The review also identifies several critical unanswered questions regarding the characteristics (functional and metabolic) of macrophages from different origins (adipose tissue, skeletal muscle, bone marrow) in obesity and how these characteristics contribute to early vs late phases of obesity. We also identified a number of new therapeutic targets that could be evaluated in future investigations. Targeting macrophage metabolism in obesity is an exciting and active area of research with significant potential to help identify new treatments to limit the detrimental effects of inflammation in obesity.

• Publication year

  2025

• Venue

  Canadian Journal of Cardiology

• Publication date

  2025-04-01

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1016/j.cjca.2025.04.017PMID 40311669
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK

  2025cited by this paper
• Metabolic flux in macrophages in obesity and type-2 diabetes

  2024cited by this paper
• Notch signaling in adipose tissue macrophages prevents diet‐induced inflammation and metabolic dysregulation

  2024cited by this paper
• β-Hydroxybutyrate suppresses M1 macrophage polarization through β-hydroxybutyrylation of the STAT1 protein

  2024cited by this paper
• A new framework for the diagnosis, staging and management of obesity in adults

  2024cited by this paper
• Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis.

  2024cited by this paper
• Macrophage energy metabolism in cardiometabolic disease

  2024cited by this paper
• Branched-chain amino acid catabolism promotes M2 macrophage polarization

  2024cited by this paper
• Itaconic acid underpins hepatocyte lipid metabolism in non-alcoholic fatty liver disease in male mice

  2023cited by this paper
• GPAT3 regulates the synthesis of lipid intermediate LPA and exacerbates Kupffer cell inflammation mediated by the ERK signaling pathway

  2023cited by this paper
• Glycolytic side pathways regulating macrophage inflammatory phenotypes and functions.

  2023cited by this paper
• GLUT3 promotes macrophage signaling and function via RAS-mediated endocytosis in atopic dermatitis and wound healing

  2023cited by this paper
• Low Glucose plus β-Hydroxybutyrate Induces an Enhanced Inflammatory Response in Yak Alveolar Macrophages via Activating the GPR109A/NF-κB Signaling Pathway

  2023cited by this paper
• xCT-mediated glutamate excretion in white adipocytes stimulates interferon-γ production by natural killer cells in obesity.

  2023cited by this paper
• Branched-Chain Amino Acid Metabolism in the Failing Heart

  2022cited by this paper
• Succinate/IL-1β Signaling Axis Promotes the Inflammatory Progression of Endothelial and Exacerbates Atherosclerosis

  2022cited by this paper
• Short Term Isocaloric Ketogenic Diet Modulates NLRP3 Inflammasome Via B-hydroxybutyrate and Fibroblast Growth Factor 21

  2022cited by this paper
• Inflammatory Macrophage Interleukin-1β Mediates High-Fat Diet-Induced Heart Failure With Preserved Ejection Fraction

  2022cited by this paper
• Aconitate decarboxylase 1 regulates glucose homeostasis and obesity in mice

  2022cited by this paper
• Ketone body β-hydroxybutyrate ameliorates colitis by promoting M2 macrophage polarization through the STAT6-dependent signaling pathway

  2022cited by this paper
• Obesity in Humans Is Characterized by Gut Inflammation as Shown by Pro-Inflammatory Intestinal Macrophage Accumulation

  2021cited by this paper
• Obesity as a multisystem disease: Trends in obesity rates and obesity‐related complications

  2021cited by this paper
• Macrophage Responses to Environmental Stimuli During Homeostasis and Disease.

  2021cited by this paper
• Adipocyte death triggers a pro-inflammatory response and induces metabolic activation of resident macrophages

  2021cited by this paper
• Putting ATM to BED: How Adipose Tissue Macrophages Are Affected by Bariatric Surgery, Exercise, and Dietary Fatty Acids.

  2021cited by this paper
• Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines

  2021cited by this paper
• Vascular Risk Reduction in Obesity through Reduced Granulocyte Burden and Improved Angiogenic Monocyte Content following Bariatric Surgery

  2020cited by this paper
• Role of Cardiac Macrophages on Cardiac Inflammation, Fibrosis and Tissue Repair

  2020cited by this paper
• New Insights on the Role of Lipid Metabolism in the Metabolic Reprogramming of Macrophages

  2020cited by this paper
• Macrophage HIF-1α Mediates Obesity-related Adipose Tissue Dysfunction via Interleukin-1 receptor-associated kinase M.

  2020cited by this paper
• Obesity, Hypertension, and Cardiac Dysfunction

  2020cited by this paper
• Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response

  2020cited by this paper
• Enhanced glycolysis and HIF-1α activation in adipose tissue macrophages sustains local and systemic interleukin-1β production in obesity

  2020cited by this paper
• Glycolysis: a key player in the inflammatory response.

  2020cited by this paper
• Metabolic Inflammation and Insulin Resistance in Obesity

  2020cited by this paper
• Myocardial Ketones Metabolism in Heart Failure: Karwi et al. Role of ketone in heart failure.

  2020cited by this paper
• KETONE METABOLISM IN THE FAILING HEART.

  2020cited by this paper
• Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology

  2020cited by this paper
• Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

  2020cited by this paper
• Kupffer Cells Sense Free Fatty Acids and Regulate Hepatic Lipid Metabolism in High-Fat Diet and Inflammation

  2020cited by this paper
• Metabolic routes in inflammation: the citrate pathway and its potential as therapeutic target.

  2020cited by this paper
• Glutamine Metabolism in Macrophages: A Novel Target for Obesity/Type 2 Diabetes

  2019cited by this paper
• Myeloid Slc2a1-Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1

  2019cited by this paper
• Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis.

  2019cited by this paper
• Mitochondrial Metabolic Reprogramming by CD36 Signaling Drives Macrophage Inflammatory Responses.

  2019cited by this paper
• Circulating glutamate level as a potential biomarker for abdominal obesity and metabolic risk.

  2019cited by this paper
• Author Correction: Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses

  2019cited by this paper
• Tissue Immune Cells Fuel Obesity-Associated Inflammation in Adipose Tissue and Beyond

  2019cited by this paper
• Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications

  2019cited by this paper
• Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype

  2019cited by this paper
• The Effect of L-Arginine Supplementation on Obesity-Related Indices: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

  2019cited by this paper
• SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity

  2019cited by this paper
• Insulin Resistance in Macrophages Alters Their Metabolism and Promotes an M2-Like Phenotype

  2019cited by this paper
• Obesity: global epidemiology and pathogenesis

  2019cited by this paper
• Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation

  2018cited by this paper
• Role of microbiota-derived lipopolysaccharide in adipose tissue inflammation, adipocyte size and pyroptosis during obesity

  2018cited by this paper
• A Role for the Krebs Cycle Intermediate Citrate in Metabolic Reprogramming in Innate Immunity and Inflammation

  2018cited by this paper
• Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1

  2018cited by this paper
• Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis

  2018cited by this paper
• Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses

  2018cited by this paper
• Intrinsic Properties of Brown and White Adipocytes Have Differential Effects on Macrophage Inflammatory Responses

  2017cited by this paper
• M1 Means Kill; M2 Means Heal

  2017cited by this paper
• Matrix metalloproteinases as regulators of inflammatory processes.

  2017cited by this paper
• α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming

  2017cited by this paper
• IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge.

  2017cited by this paper
• SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes

  2017cited by this paper
• Role of innate and adaptive immunity in obesity-associated metabolic disease

  2017cited by this paper
• Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation

  2016cited by this paper
• Fatty acid synthesis configures the plasma membrane for inflammation in diabetes

  2016cited by this paper
• Local proliferation initiates macrophage accumulation in adipose tissue during obesity

  2016cited by this paper
• Fatty acid oxidation in macrophage polarization

  2016cited by this paper
• Macrophage fatty acid oxidation and its roles in macrophage polarization and fatty acid-induced inflammation.

  2016cited by this paper
• Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation.

  2016cited by this paper
• Colonic Pro-inflammatory Macrophages Cause Insulin Resistance in an Intestinal Ccl2/Ccr2-Dependent Manner.

  2016cited by this paper
• Metabolic Reprogramming Mediated by the mTORC2-IRF4 Signaling Axis Is Essential for Macrophage Alternative Activation.

  2016cited by this paper
• Metformin and Inflammation: Its Potential Beyond Glucose-lowering Effect.

  2015cited by this paper
• Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation.

  2015cited by this paper
• Ketone body β-hydroxybutyrate blocks the NLRP3 inflammasome-mediated inflammatory disease

  2015cited by this paper
• Antidiabetic agents: Potential anti-inflammatory activity beyond glucose control.

  2015cited by this paper
• NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation.

  2015cited by this paper
• Arginase inhibition ameliorates adipose tissue inflammation in mice with diet-induced obesity.

  2015cited by this paper
• Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization.

  2015cited by this paper
• Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus

  2014cited by this paper
• Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target

  2014cited by this paper
• Fatty acid oxidation is dispensable for human macrophage IL-4-induced polarization.

  2014cited by this paper
• Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation.

  2014cited by this paper
• Testing the role of myeloid cell glucose flux in inflammation and atherosclerosis.

  2014cited by this paper
• Metabolic Reprogramming of Macrophages

  2014cited by this paper
• ß-Hydroxybutyrate Activates the NF-κB Signaling Pathway to Promote the Expression of Pro-Inflammatory Factors in Calf Hepatocytes

  2014cited by this paper
• BHBA Suppresses LPS-Induced Inflammation in BV-2 Cells by Inhibiting NF-κB Activation

  2014cited by this paper
• Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages.

  2014cited by this paper
• Influence of Gut Microbiota on Subclinical Inflammation and Insulin Resistance

  2013cited by this paper
• Intraperitoneal Injection of Clodronate Liposomes Eliminates Visceral Adipose Macrophages and Blocks High-fat Diet-induced Weight Gain and Development of Insulin Resistance

  2013cited by this paper
• Differential effects of endurance training and weight loss on plasma adiponectin multimers and adipose tissue macrophages in younger, moderately overweight men.

  2013cited by this paper
• Macrophage Glucose-6-Phosphate Dehydrogenase Stimulates Proinflammatory Responses with Oxidative Stress

  2013cited by this paper
• Succinate is an inflammatory signal that induces IL-1β through HIF-1α

  2013cited by this paper
• Expression and activity of the TLR4/NF-κB signaling pathway in mouse intestine following administration of a short-term high-fat diet

  2013cited by this paper
• Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation.

  2013cited by this paper
• High-Fat Diet Reduces the Formation of Butyrate, but Increases Succinate, Inflammation, Liver Fat and Cholesterol in Rats, while Dietary Fibre Counteracts These Effects

  2013cited by this paper
• The function and the role of the mitochondrial glycerol-3-phosphate dehydrogenase in mammalian tissues.

  2013cited by this paper

• Probiotic extracellular vesicles reprogram macrophage immunometabolism: From gut crosstalk to host health

  2026cites this paper
• 4-week aerobic exercise training regulates systemic macrophage polarization in obese mice

  2026cites this paper
• Metabolic immunobridge: Could adipose-derived extracellular vesicles be the missing link between obesity, autoimmunity, and drug-induced hepatotoxicity?

  2025cites this paper
• Neuroendocrine-immune crosstalk bridge: could gut-derived serotonin-loaded extracellular vesicles be the hidden connector between depression, obesity, and non-alcoholic fatty liver disease?

  2025cites this paper
• Targeting macrophage glucose metabolism: Polysaccharide-iron nanozyme-mediated reactive oxygen species/iron homeostasis restoration ameliorates inflammatory bowel disease with anemia comorbidity.

  2025cites this paper
• Quinoa Ameliorates High‐Fat Diet‐Induced Obesity in Female Mice by Regulating Gut Microbiota and Adipogenesis

  2025cites this paper
• Macrophage Phenotypic Switch and Obesity-Associated Metabolic Risk: Mechanisms and Targets

  2025cites this paper
• Obesity in Cardiovascular Disease Prevention and Treatment - A Topic Getting "Heavier" as We Speak.

  2025cites this paper