Immunometabolism in obesity

Immunometabolism in obesity is the study of how nutrient excess and adipose tissue stress reshape immune cell metabolism to sustain chronic low-grade inflammation. It integrates the metabolic reprogramming of macrophages, T cells, and dendritic cells with the systemic consequences of obesity-associated inflammation.

Obesity as a chronic inflammatory state

Obesity is a chronic metabolic condition characterized by excess adipose tissue accumulation and increased risk of type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), cardiovascular disease, and several inflammatory disorders. Beyond energy storage, obesity represents a state of chronic low-grade inflammation, often termed metaflammation, in which nutrient excess and altered adipocyte secretory profiles reprogram immune cell metabolism.¹

The field of immunometabolism examines how metabolic pathways regulate immune cell function and how immune responses reciprocally influence tissue and systemic metabolism. In obesity, immune cells are exposed to glucose, fatty acids, inflammatory cytokines, chemokines, oxidative stress, and adipocyte-derived mediators. These signals reshape macrophage, T cell, B cell, and dendritic cell behavior, contributing to insulin resistance and disease progression.¹

Adipose tissue as an immune–metabolic organ

Adipose tissue is now recognized as an active endocrine and immune organ rather than a passive lipid depot. It hosts macrophages, T cells, B cells, dendritic cells, eosinophils, innate lymphoid cells, and natural killer cells, which collectively regulate tissue homeostasis and inflammation.⁴

In lean adipose tissue, immune cells support an anti-inflammatory environment that preserves insulin sensitivity. In obesity, adipocyte hypertrophy, hypoxia, lipid overload, mitochondrial stress, and cell death promote cytokine and chemokine release, driving immune cell recruitment and activation. This establishes a feed-forward loop in which metabolic stress promotes inflammation, and inflammation further worsens metabolic dysfunction.²,³

Macrophage metabolic reprogramming in obesity

Macrophages are among the most abundant immune cells in adipose tissue and central drivers of obesity-associated inflammation. During obesity, adipose tissue macrophages accumulate in visceral depots and contribute to chronic inflammation and insulin resistance.³

In lean tissue, macrophages support tissue maintenance and anti-inflammatory functions. In obesity, they become more inflammatory and metabolically activated, displaying elevated glycolysis alongside oxidative phosphorylation compared with macrophages from lean animals.³

A key mechanism involves HIF-1α activation, which induces glycolytic genes and supports production of inflammatory mediators such as IL-1β. In obese adipose tissue macrophages, HIF-1α activation can occur in both hypoxic and non-hypoxic contexts, suggesting that fatty acids and inflammatory signals generate a pseudohypoxic response.² Relevant glycolytic markers include GLUT1 (glucose uptake) and enzymes such as HK1, GAPDH, PKM, and LDH.

Lipid metabolism and macrophage inflammation

Obesity exposes adipose tissue immune cells to elevated free fatty acids released from enlarged adipocytes. These fatty acids promote macrophage activation, inflammatory cytokine production, and metabolic stress.³ Lipid-handling targets relevant to obesity immunometabolism include:

• Fatty acid uptake: CD36/FAT
• Fatty acid synthesis and storage: ACACA, ACLY, FASN, DGAT1
• Mitochondrial fatty acid oxidation: CPT1A, ACADM/MCAD

T cell imbalance in obese adipose tissue

T cells are important regulators of adipose tissue inflammation. In healthy adipose tissue, regulatory and anti-inflammatory T cell populations maintain metabolic balance. In obesity, the balance shifts toward proinflammatory T cell responses, including increased Th1, Th17, and CD8+ T cell activity, with reduced regulatory T cell (Treg) function in many contexts.⁴,⁵

The Th17/Treg axis is particularly relevant in obesity and metabolic disease. Th17 cells promote inflammation, while Tregs suppress excessive responses and maintain immune tolerance.⁵ T cell function is also shaped by metabolism: activated T cells increase glycolysis to support proliferation and cytokine production, while lipid metabolism influences effector differentiation and inflammatory output.

Fatty acid synthesis and Th17 biology

Lipid metabolism has a specific role in Th17 biology. Obesity drives Th17 differentiation by inducing the lipid metabolic enzyme ACC1 (encoded by ACACA), which modulates RORγt function during Th17 development.⁶,⁷ This supports the inclusion of ACACA, FASN, and ACLY when investigating fatty acid synthesis in obesity-associated T cell inflammation, interpreted alongside functional readouts such as IL-17A, RORγt, and T cell subset identification.

CD8+ T cells, fatty acid oxidation and obesity-associated cancer

Obesity can also alter CD8+ T cell metabolism. In obesity-promoted breast cancer models, STAT3 activation increased fatty acid oxidation in CD8+ effector T cells, suppressing glycolysis and impairing anti-tumor immune function.⁸ This provides a rationale for including fatty acid oxidation markers such as CPT1A and ACADM/MCAD when studying obesity-associated immune dysfunction, particularly in cancer immunometabolism.

Mitochondrial metabolism and oxidative stress

Mitochondrial dysfunction and oxidative stress are core features of obesity-associated metabolic inflammation. In white adipose tissue, nutrient excess increases mitochondrial substrate load, alters electron transport chain activity, and elevates reactive oxygen species (ROS) production. Obese adipose tissue is also associated with reduced antioxidant capacity.¹⁰

Relevant mitochondrial targets include CS, IDH2, OGDH, SDHB, cytochrome c, ATP5A, AIF, VDAC1/Porin, VDAC2, MFN2, and mtTFA, which capture TCA cycle activity, oxidative phosphorylation, mitochondrial membrane function, dynamics, and transcriptional regulation. Redox-related targets such as GSS, PRDX2/PRP, and SIRT1 support the study of oxidative stress and antioxidant defense.

Dendritic cells and fatty acid oxidation

Dendritic cells (DCs) are professional antigen-presenting cells whose function is disrupted by obesity. High-fat diet-induced obesity alters DC transcriptional programs linked to lipid metabolism and mitochondrial function. DCs from obese mice show increased mitochondrial respiration driven by fatty acid oxidation, leading to ROS accumulation and impaired antigen presentation to T cells.⁹

This supports the relevance of CPT1A, oxidative phosphorylation markers (ATP5A, SDHB), and oxidative stress markers (PRDX2/PRP, GSS, SIRT1) in obesity immunometabolism studies.

Amino acid, glutamine, and nucleotide metabolism

Although glycolysis and lipid metabolism dominate the obesity immunometabolism literature, amino acid and nucleotide metabolism also shape immune cell behavior. Glutamine metabolism supports immune cell activation, proliferation, biosynthesis, and redox balance. Targets such as ASCT2, CD98, GLS, and GLUD1/GLUD2 are useful for studying glutamine uptake and catabolism in activated immune cells.

Proliferating immune cells also require nucleotides, reducing power, and biosynthetic intermediates from one-carbon and pentose phosphate pathways. Targets such as ASS1, CAD, DPD, G6PD, SHMT2/SHMT, TKT, and ENT1 are relevant for broader metabolic profiling panels, particularly in chronically activated populations.

Cytokines and chemokines in obesity

Cytokines and chemokines link adipose tissue stress to immune cell recruitment. Obese adipose tissue releases proinflammatory mediators that drive macrophage accumulation, insulin resistance, and MASLD.¹¹

Human studies show that CC chemokines and their receptors, including CCL2, CCL3, CCL5, CCL7, CCL8, CCL11, CCR1, CCR2, CCR3, and CCR5,are increased in subcutaneous and visceral adipose tissue of individuals with obesity and correlate with macrophage marker expression and systemic inflammation.¹²,¹³ Chemokine biology therefore explains how metabolically stressed adipose tissue recruits inflammatory immune cells

Key target areas for obesity immunometabolism research

Frequently asked questions

References

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