Adipose tissue dysfunction in obesity and type 2 diabetes: the role of DNA methylation linking adipogenesis to metabolic disease

Abstract Adipose tissue plasticity, sustained by the recruitment and differentiation of adipocyte precursor cells (APCs), is a key determinant of metabolic health. Failure of this adaptive program, rather than fat mass per se, represents an early contributing factor in the progression toward insulin resistance (IR) and type 2 diabetes (T2D). Increasing evidence identifies impaired APC function and premature cellular senescence as central mechanistic drivers of adipose tissue dysfunction. In this context, the interplay between DNA methylation and cellular senescence emerges as a central axis linking impaired adipogenesis to adipose tissue dysfunction. Emerging evidence highlights epigenetic dysregulation, particularly aberrant DNA methylation, as a pivotal mechanism controlling adipogenesis, senescence, and metabolic flexibility. DNA methylation dynamically modulates transcriptional programs governing adipocyte commitment and maturation through the interplay of DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes. In obesity and T2D, disruption of this DNMT/TET balance promotes maladaptive remodeling, persistent inflammatory signaling, and premature cellular senescence, with locus-specific methylation changes affecting key adipogenic regulators that limit APC commitment and differentiation, as documented in human adipose tissue across obesity and diabetes. Senescent APCs acquire a pro-inflammatory secretory phenotype, known as the senescence-associated secretory phenotype (SASP), that spreads dysfunction to neighboring cells and amplifies systemic IR. Understanding this epigenetic–senescence axis may provide a framework for therapeutic intervention. Epigenetic modulators such as DNMT inhibitors (DNMTis) and TET activators, alongside senolytic and senomorphic agents, have shown promising preclinical results in restoring adipose function. Complementary lifestyle interventions, including caloric restriction (CR) and exercise, further remodel the adipose epigenome toward a metabolically favorable state. Targeting both epigenetic mechanisms and cellular senescence may represent a promising strategy to improve adipose function and metabolic outcomes and restore metabolic flexibility.