The Role of Immunometabolic Dysregulation in Obesity-Associated Cardiovascular Risk: A Narrative Review
DOI:
https://doi.org/10.66687/jebmr.2.1.2026.29Palabras clave:
inflammation, mitochondrial dysfunction, ANT2, atherosclerosis, cardiovascular disease, immunometabolismResumen
Background: Obesity is a major global health problem and an established risk factor for cardiovascular disease (CVD). Beyond traditional risk factors, chronic low-grade inflammation and immune-cell metabolic dysfunction may provide a mechanistic link between obesity and vascular disease.
Objective: To synthesise current evidence on adipose tissue inflammation, monocyte and macrophage immunometabolic reprogramming, mitochondrial dysfunction, and the pathways connecting obesity with cardiovascular risk, while identifying emerging therapeutic targets.
Methods: A narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar for studies published from 2000 to July 2026. Original human, animal, and in vitro studies addressing adipose tissue macrophages, immunometabolic reprogramming, inflammatory signalling, metabolic dysfunction, or cardiovascular outcomes were included and synthesised thematically.
Results: Obesity was consistently associated with adipose tissue macrophage recruitment and expansion, particularly through CCR2/CCL2 signalling, together with pro-inflammatory metabolic reprogramming characterised by increased glycolysis, altered fatty-acid oxidation, mitochondrial dysfunction, reactive oxygen species production, and activation of HIF-1α and NF-κB. The resulting release of TNF-α, IL-6, and IL-1β contributes to insulin resistance, endothelial dysfunction, hepatic steatosis, and atherosclerosis. Shared inflammatory and metabolic pathways were identified in obese adipose tissue and atherosclerotic lesions. However, a subgroup of individuals with obesity showed little adipose inflammation and relatively preserved vascular function, indicating that adipose tissue quality may be more informative than adiposity alone. Potential therapeutic targets include CCR2, AMPK, ANT2, SIRT3, mitochondrial reactive oxygen species, and dietary macronutrient composition.
Conclusion: Immunometabolic dysregulation appears to be a central mechanism linking obesity with cardiovascular disease. Strategies that restore immune-cell metabolism, preserve mitochondrial function, and reduce adipose tissue inflammation may complement conventional weight-management approaches, although further longitudinal and clinical studies are required.
Referencias
Ostojic S, Phelps NH, Singleton RK, et al.: Worldwide trends in the underweight and obesity from 1990 to 2022: a pooled analysis of 3,633 population-representative studies with 222 million school-aged children, adolescents, and adults. 2024.
Lopez-Jimenez F, Di Cesare M, Powis J, et al.: The weight of cardiovascular diseases: addressing the global cardiovascular crisis associated with obesity. Global heart. 2025, 20:68-68.
Diseases GBoC, Collaborators R: Global, regional, and national burden of cardiovascular diseases and risk factors in 204 countries and territories, 1990-2023. Journal of the American College of Cardiology. 2025, 86:2167-2243.
Zalesin KC, Franklin BA, Miller WM, Peterson ED, McCullough PA: Impact of obesity on cardiovascular disease. Endocrinology and metabolism clinics of North America. 2008, 37:663-684.
Tomić Naglić D, Manojlović M, Pejaković S, et al.: Inflammatory Memory of Adipose Tissue Macrophages: From CD68 Footprint to Cardiometabolic and Cancer Risk During Weight Cycling. Int J Mol Sci. 2026, 27. 10.3390/ijms27104203
Khwatenge CN, Pate M, Miller LC, Sang Y: Immunometabolic Dysregulation at the Intersection of Obesity and COVID-19. Front Immunol. 2021, 12:732913. 10.3389/fimmu.2021.732913
Penninx B, Lange SMM: Metabolic syndrome in psychiatric patients: overview, mechanisms, and implications. Dialogues Clin Neurosci. 2018, 20:63-73. 10.31887/DCNS.2018.20.1/bpenninx
Long J, Zhao J, Gu X, Huang C: Post-transplant diabetes mellitus after kidney transplantation: pathogenesis, risk factors, and management strategies. Front Endocrinol (Lausanne). 2026, 17:1829579. 10.3389/fendo.2026.1829579
Milaneschi Y, Lamers F, Peyrot WJ, et al.: Genetic Association of Major Depression With Atypical Features and Obesity-Related Immunometabolic Dysregulations. JAMA Psychiatry. 2017, 74:1214-1225. 10.1001/jamapsychiatry.2017.3016
Peikert A, Vacca A, Norata GD, Schiattarella GG, Osto E: Cellular Interactions and Immunometabolic Mechanisms in Heart Failure With Preserved Ejection Fraction: From Molecular Mechanisms to Clinical Evidence. Circ Heart Fail. 2026, 19:e012674. 10.1161/circheartfailure.125.012674
Oleinika K, Slisere B, Catalán D, Rosser EC: B cell contribution to immunometabolic dysfunction and impaired immune responses in obesity. Clin Exp Immunol. 2022, 210:263-272. 10.1093/cei/uxac079
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW: Obesity is associated with macrophage accumulation in adipose tissue. The Journal of clinical investigation. 2003, 112:1796-1808.
Weisberg SP, Hunter D, Huber R, et al.: CCR2 modulates inflammatory and metabolic effects of high-fat feeding. The Journal of clinical investigation. 2006, 116:115-124.
Galic S, Fullerton MD, Schertzer JD, et al.: Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. The Journal of clinical investigation. 2011, 121:4903-4915.
Moon J-S, da Cunha FF, Huh JY, et al.: ANT2 drives proinflammatory macrophage activation in obesity. JCI insight. 2021, 6:e147033.
Moreno-Viedma V, Amor M, Sarabi A, et al.: Common dysregulated pathways in obese adipose tissue and atherosclerosis. Cardiovascular diabetology. 2016, 15:120.
Radushev V, Karkossa I, Berg J, et al.: Dysregulated cytokine and oxidative response in hyper-glycolytic monocytes in obesity. Frontiers in Immunology. 2024, 15:1416543.
Smeehuijzen L, Gijbels A, Nugteren-Boogaard JP, et al.: Immunometabolic signatures of circulating monocytes in humans with obesity and insulin resistance. Diabetes. 2024, 73:1112-1121.
Strand K, Stiglund N, Haugstøyl ME, et al.: Subtype-specific surface proteins on adipose tissue macrophages and their association to obesity-induced insulin resistance. Frontiers in Endocrinology. 2022, 13:856530.
Apovian CM, Bigornia S, Mott M, et al.: Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects. Arteriosclerosis, thrombosis, and vascular biology. 2008, 28:1654-1659.
Farb MG, Bigornia S, Mott M, et al.: Reduced adipose tissue inflammation represents an intermediate cardiometabolic phenotype in obesity. Journal of the American College of Cardiology. 2011, 58:232-237.
Makkonen J, Westerbacka J, Kolak M, et al.: Increased expression of the macrophage markers and of 11β-HSD-1 in subcutaneous adipose tissue, but not in cultured monocyte-derived macrophages, is associated with liver fat in human obesity. International journal of obesity. 2007, 31:1617-1625.
Ahlin S, Sjöholm K, Jacobson P, et al.: Macrophage gene expression in adipose tissue is associated with insulin sensitivity and serum lipid levels independent of obesity. Obesity. 2013, 21:E571-E576.
Kunz HE, Hart CR, Gries KJ, et al.: Adipose tissue macrophage populations and inflammation are associated with systemic inflammation and insulin resistance in obesity. American Journal of Physiology-Endocrinology and Metabolism. 2021, 321:E105-E121.
Parvaresh Rizi E, Baig S, Shabeer M, et al.: Meal rich in carbohydrate, but not protein or fat, reveals adverse immunometabolic responses associated with obesity. Nutrition journal. 2016, 15:100.
Tercan H, Cossins BC, van Deuren RC, et al.: Association between clonal hematopoiesis driver mutations, immune cell function, and the vasculometabolic complications of obesity. Journal of the American Heart Association. 2024, 13:e031665.
Valero-Muñoz M, Cooper HL, Li S, et al.: Metabolic dysregulation in the heart in obesity-associated HFpEF. Frontiers in Cardiovascular Medicine. 2025, 12:1678992.
Wang Y, Viollet B, Terkeltaub R, Liu-Bryan R: AMP-activated protein kinase suppresses urate crystal-induced inflammation and transduces colchicine effects in macrophages. Ann Rheum Dis. 2016, 75:286-294. 10.1136/annrheumdis-2014-206074
Kardinal R, Wachten D: Macrophages in metaflammation – fueling chronic inflammation in metabolic disease. Pflügers Archiv - European Journal of Physiology. 2025, 478:10. 10.1007/s00424-025-03141-0
Jaroch A: Metabolomics of abdominal adipose tissue samples collected from patients with obesity – a critical review. Molecular and Cellular Biochemistry. 2026, 481:29-39. 10.1007/s11010-025-05399-5
Hinojosa Vera K, Hemakumar C, Bilachi R, Ramirez D, Gomez Mejiba S: Macrophage Phenotypic Switch and Obesity‐Associated Metabolic Risk: Mechanisms and Targets. Oxidative Medicine and Cellular Longevity. 2025, 2025:6710641.
Subramaniyan V, Logesh R, Jeyabalan S, et al.: Pathophysiological impacts of lifestyle transitions on obesity: A molecular overview of metabolic dynamics. Obesity Medicine. 2026, 61:100705. https://doi.org/10.1016/j.obmed.2026.100705
Turner L, Wanasinghe AI, Brunori P, Santosa S: Is Adipose Tissue Inflammation the Culprit of Obesity‐Associated Comorbidities? Obesity Reviews. 2025, 26:e13956.
Wong A, Sun Q, Latif II, Karwi QG: Macrophage energy metabolism in cardiometabolic disease. Molecular and Cellular Biochemistry. 2025, 480:1763-1783. 10.1007/s11010-024-05099-6
