Stress-coping phenotypes shape adipose tissue function and plasticity and modulate metabolic resilience

Our previous findings demonstrated that stress resilience confers metabolic protection in high-fat diet (HFD)-fed mice. Recognizing the central role of adipose tissue in the pathogenesis of obesity comorbidities, this study aimed to define how stress resilience shapes adipose tissue function. Stress-resilient (Dominant, Dom) and stress-vulnerable (Submissive, Sub) mice were examined under standard (STD) or HFD. Metabolic, molecular, and transcriptomic analyses were performed in epididymal and inguinal white adipose tissue (eWAT and iWAT), and the effects of PPARgamma activator (pioglitazone) and antidepressant (paroxetine) were investigated. Stromal vascular fraction (SVF) cells were isolated to assess adipogenic potential. Sub mice developed glucose intolerance under HFD, accompanied by impaired insulin-induced Akt phosphorylation, and reduced glucose uptake in WAT, whereas Dom mice remained metabolically protected. Sub WAT exhibited adipocyte hypertrophy, an unfavorable leptin-to-adiponectin ratio, and depot-specific suppression of BCAA catabolic enzymes. RNA sequencing revealed transcriptomic divergence between strains, with Sub mice showing downregulation of adipogenesis under STD conditions. Functional analyses confirmed reduced proliferative and adipogenic potential of SVF cells, derived from Sub mice under both dietary conditions. In contrast, Dom-derived adipocytes displayed higher Glut4 and Ucp1 and an elevated adiponectin-to-leptin mRNA expression ratio. Pioglitazone enhanced adipogenesis, insulin sensitivity, and prevented hepatic steatosis in Sub mice, although this was not accompanied by improved glucose tolerance. Paroxetine treatment normalized behavioral deficits in Sub mice and improved adipogenesis toward a Dom-like profile. In summary, this study demonstrates that impaired stress coping drives defects in adipose progenitor function, leading to maladaptive WAT expansion and increased susceptibility to obesity-related metabolic disease.