Abstract

Adipose-derived stem cells (ADSCs), also called adipose stromal/stem cells, reside in the stromal vascular 
fraction of white adipose tissue and are essential for adipose tissue plasticity, healthy expansion and 
immunometabolic balance. In physiological states, ADSCs support adipocyte turnover, promote angiogenesis 
and exert immunoregulatory and anti-inflammatory actions, allowing subcutaneous fat to buffer caloric excess 
without provoking systemic insulin resistance.In obesity, however, chronic nutrient overload, hypoxia, oxidative 
stress and low-grade inflammation converge on ADSCs, driving senescence, epigenetic reprogramming, loss of 
proliferative capacity and skewed differentiation. Human and animal studies show that obesity and type 2 
diabetes (T2D) are associated with early senescence and mitochondrial dysfunction in ADSCs, reduced 
clonogenicity and adipogenic potential, pro-fibrotic and pro-inflammatory secretomes and altered crosstalk with 
immune cells. These changes compromise adipose expandability, promote adipocyte hypertrophy, fibrosis and 
adipose inflammation and favor ectopic lipid deposition in liver and muscle, thereby accelerating the transition 
from obesity to insulin resistance and overt T2D. At the same time, ADSCs retain therapeutic potential: 
exogenous or rejuvenated ADSCs can ameliorate insulin resistance and β-cell dysfunction in preclinical diabetes 
models through anti-inflammatory and pro-regenerative mechanisms. This review synthesizes current evidence 
on how ADSC dysfunction contributes mechanistically to the obesity–diabetes transition, and discusses 
emerging strategies to preserve or restore ADSC function, including senescence-targeted interventions, niche 
modulation and cell-based therapies.