Decoding Immunometabolic Dynamics of Adipose Tissue in Obesity: Evolving Evidence and Way Forward

Obesity is a prevalent global health condition associated with an increased risk of cardiovascular and metabolic diseases. Despite the transformative impact of GLP-1 receptor agonists and dual or triple incretin agonists in obesity management, a significant subset of patients develops therapeutic resistance, exhibits no weight loss, or experiences weight regain after treatment discontinuation. These limitations underscore critical gaps in understanding the biological mechanisms underlying the heterogeneity in drug responsiveness. Growing evidence indicates that adipose tissue is a dynamic immunometabolic organ in which chronic low-grade inflammation perturbs metabolic homeostasis and modulates the therapeutic responsiveness. This Review integrates emerging mechanistic, translational, and multiomics evidence on obesity-induced remodeling of adipose immune-cell niches. It also delineates the effects of these alterations, including impaired lipolysis, insulin resistance, defective thermogenesis, and resistance to weight loss. Overall, this Review highlights adipose tissue immunometabolism as a central yet often underappreciated contributor to therapeutic responsiveness and a promising target for future obesity therapies.