Abstract

Adipose tissue is now recognized as an immune organ as much as a fat depot. In obesity, expansion and stress 
of white adipose tissue (WAT) drive a coordinated rewiring of immune and metabolic pathways 
“immunometabolism” that links weight gain to insulin resistance and type 2 diabetes (T2D). Lean adipose tissue 
is enriched in type 2 immune cells (M2-like macrophages, eosinophils, ILC2s, regulatory T cells), which support 
insulin sensitivity, lipolysis, and thermogenesis. With chronic overnutrition, hypertrophic adipocytes become 
hypoxic, stressed, and dying; chemokines and lipotoxic signals recruit and reprogram myeloid and lymphoid 
cells toward pro-inflammatory, glycolysis-dependent phenotypes, forming crown-like structures (CLS) and 
amplifying cytokine production. Adipose tissue macrophages (ATMs) emerge as central hubs controlling lipid 
handling, mitochondrial function, thermogenesis, and systemic glucose homeostasis. This review synthesizes 
current knowledge on adipose tissue immunometabolism as a unifying driver of obesity and T2D. We outline 
the cellular landscape of adipose immune cells, their metabolic programs, and how obesogenic cues reshape 
ATM, T-cell, and innate lymphoid cell states. We then discuss how these immunometabolic shifts impair 
adipocyte biology, disrupt endocrine outputs, and propagate systemic insulin resistance and β-cell stress. 
Protective pathways involving brown and beige fat, type 2 immunity, and mitochondrial crosstalk are contrasted 
with inflammatory circuits. Finally, we examine evidence that lifestyle, weight loss, and pharmacologic therapies 
can remodel adipose immunometabolism, and highlight emerging immunometabolic targets and biomarkers for 
precision treatment of obesity-driven T2D.