Abstract

Obesity is the strongest modifiable driver of type 2 diabetes (T2D), yet the mechanistic bridge between excess 
adiposity and systemic dysglycemia is increasingly recognized as dysfunction of adipose tissue (AT) rather than 
fat mass per se. In health, subcutaneous white adipose tissue (WAT) expands via adipogenesis to safely store 
lipid, secretes insulin-sensitizing adipokines, and communicates with liver, muscle, pancreas, brain, and immune 
cells to maintain fuel homeostasis. In obesity, this plasticity is exceeded, precipitating adipocyte hypertrophy, 
depot-specific hypoxia, extracellular-matrix remodeling and fibrosis, mitochondrial and endoplasmic-reticulum 
stress, and chronic low-grade inflammation (metaflammation). These insults drive insulin resistance, 
catecholamine resistance, dysregulated lipolysis, and ectopic lipid deposition with lipotoxic signaling, ultimately 
burdening hepatic glucose production, myocellular glucose uptake, and β-cell function. Emerging insights into 
AT endocrine and paracrine factors classical adipokines (adiponectin, leptin), lipokines, cytokines, and 
extracellular vesicles highlight complex bidirectional cross-talk across organs. Converging mechanisms suggest 
therapeutic opportunities: weight loss through lifestyle and surgery; insulin-sensitizing agents (metformin, 
thiazolidinediones); incretin-based poly-agonists; SGLT2 inhibition; and investigational approaches targeting 
inflammation, fibrosis, mitochondrial quality control, and thermogenic/beige fat recruitment. Precision 
strategies that integrate depot heterogeneity, immunometabolic states, and multi-omics phenotyping may 
enable individualized interventions that restore AT health rather than merely shrinking fat mass. This review 
synthesizes current concepts linking AT dysfunction with T2D pathogenesis, surveys therapeutic avenues from 
lifestyle to next-generation pharmacology, and outlines outstanding questions for clinical translation.