The Role of Adipose Tissue Macrophages in Adipose Tissue Fibrosis.

Adipose tissue macrophages (ATMs) are a key immune cell population linking obesity, chronic low-grade inflammation, extracellular matrix (ECM) remodeling and systemic metabolic dysfunction. Recent single-cell and spatial omics studies indicate that ATMs cannot be adequately described by the traditional M1/M2 dichotomy. Instead, they form a continuum of states that includes lipid-associated macrophages (LAMs), perivascular macrophages (PVMs), sympathetic neuron-associated macrophages (SAMs), septal adipose tissue macrophages (sATMs) and candidate collagen-expressing macrophages (CEMs). Distinct ATM subsets can exert opposing effects, including inflammation, lipid buffering, tissue repair and fibrosis, depending on adipose depot, species, obesity stage and the mechanical microenvironment. In this review, we discuss adipose tissue fibrosis within a context-dependent framework of ATM-regulated fibro-inflammation. We evaluate the roles of ATMs in ECM deposition, adipose progenitor remodeling, mechano-biochemical positive feedback and the adipose tissue-liver axis. We focus on the interactions among TGF-beta/Smad, Piezo1/YAP, integrin/FAK, MINCLE-OSM, extracellular vesicles and adipocyte-derived signals, particularly adiponectin, and explain how these pathways affect tissue stiffening, ectopic lipid deposition and MASLD/MASH progression. We also stratify the evidence supporting CCR2/CCR5 blockade, macrophage metabolic reprogramming, Piezo1/integrin-targeted mechanotransduction, CAR-M therapy, RNAi and engineered macrophage therapies. This distinction separates strategies with metabolic or preclinical support from emerging approaches that remain at the proof-of-concept stage. Together, this review provides a more precise mechanistic framework for understanding obesity-associated adipose tissue fibrosis and its metabolic consequences.