Immunometabolism Mechanisms Linking Inflammation and Obesity

Immunometabolism is an expanding field that examines the bidirectional interactions between immune signaling and metabolic regulation, with particular relevance to obesity and its associated complications. Obesity is a major risk factor for insulin resistance, type 2 diabetes, and cardiovascular disease, and is characterized by chronic, low-grade inflammation within adipose tissue. Low-grade chronic inflammation is also linked to the physiologic adaptive immune response known as “para-inflammation,” which can contribute to disease progression and affect recruitment of inflammatory cells in tissue. This inflammatory milieu disrupts adipose tissue function, impairs systemic metabolic homeostasis, and contributes to disease progression. Despite growing knowledge of immune cell involvement in obese adipose tissue, the immune programs and metabolic cues that initiate, sustain, or resolve inflammation remain incompletely defined. Recent advances in single-cell and spatial profiling technologies have revealed substantial heterogeneity among adipose-resident and infiltrating immune cells and highlighted their roles in tissue remodeling and metabolic dysfunction. In this context, TGM2-expressing macrophages have emerged as a population of interest due to their potential involvement in extracellular matrix remodeling, cytokine production, efferocytosis, and regulation of adipocyte health, as well as other metabolically very active CD9 or Trem2 positive ATM. However, their origin, activation states, spatial distribution, and functional relevance across different adipose depots and metabolic states remain unclear. Moreover, key questions persist regarding depot- and sex-specific immune adaptations, the reversibility of immune remodeling with weight loss or therapeutic intervention, and the mechanistic links between local adipose immune activity and whole-body metabolic outcomes.

The aim of this Research Topic is to advance understanding of how immune remodeling within adipose tissue contributes to obesity pathophysiology and metabolic dysfunction. We seek studies that define immune cell identity, activation states, and spatial organization in metabolically active peripheral tissues during obesity, particularly in adipose tissue and liver, with emphasis on macrophage heterogeneity, fibrosis, and function. Contributions addressing immune–adipocyte cross-talk, extracellular matrix dynamics, and the integration of inflammatory and metabolic signaling pathways are encouraged. In addition, this Research Topic welcomes investigations into therapeutic strategies that target immunometabolic pathways, including pharmacological, biological, and lifestyle-based interventions, and their translational relevance for improving metabolic health in obesity.
This Research Topic welcomes original research articles, reviews, and translational studies spanning basic, preclinical, and clinical research. Topics of interest include, but are not limited to:

- Molecular and cellular mechanisms linking adipose immune remodeling to insulin resistance and metabolic dysfunction
- Single-cell and spatial analyses of immune cell heterogeneity and niche organization in obese adipose tissue
- Cross-talk between macrophages, adipocytes, endothelial cells, and stromal cells during adipose tissue expansion and dysfunction
- Cross-talk among hepatocytes, kupffer cells, and hepatic stellate cells (HSCs) in the context of MAFLD and liver fibrosis. Depot-specific (visceral vs. subcutaneous), sex-specific, and longitudinal immune–metabolic adaptations during weight gain or weight loss
- Therapeutic interventions targeting immunometabolic pathways in obesity, with integrated metabolic and inflammatory outcomes
- Translational and human studies linking adipose immune signatures to metabolic phenotypes, disease severity, and treatment response