Adipose tissue macrophages in metabolic inflammation and disease: Insights from single-cell and multi-omics studies.

Abstract

Adipose tissue macrophages (ATMs) have emerged as central regulators at the interface of immunity and metabolism. Accumulating evidence indicates that ATMs play multifaceted roles in the initiation and progression of obesity-associated metabolic disorders, including type 2 diabetes and non-alcoholic fatty liver disease. This review synthesizes current knowledge on ATM functional diversity, with a particular focus on microenvironment-driven polarization, metabolic reprogramming, intercellular communication, and cross-organ immune regulation. We highlight how lipid overload, inflammatory mediators, and oxidative stress cooperatively shape ATM fate and function, endowing these cells with dual capacities to preserve tissue homeostasis or to propagate chronic metabolic inflammation. From a translational perspective, ATMs represent attractive biomarkers and therapeutic targets. Emerging strategies-including small-molecule modulators, natural compounds, and macrophage-targeted delivery systems such as miRNA-loaded nanoparticles-have demonstrated promise in reprogramming ATM phenotypes and alleviating metabolic dysfunction. Moreover, recent advances in single-cell omics, spatial transcriptomics, and fate-mapping technologies are redefining our understanding of ATM heterogeneity and temporal dynamics in human adipose tissue, thereby enabling precision immunometabolic interventions. A deeper elucidation of the immunometabolic mechanisms governing ATMs will provide both a conceptual framework and therapeutic foundation for the precision treatment of metabolic diseases.