Obesity is a major global health challenge and a key driver of type 2 diabetes mellitus, cardiovascular disease, and metabolic syndrome. Although pharmacological therapies and bariatric surgery have improved both short- and long-term outcomes, with GLP-1 receptor agonists now demonstrating cardiovascular and heart-failure benefits beyond weight reduction (SELECT, SUMMIT), durable and broadly applicable treatments for all patients remain limited. In this context, mesenchymal stem/stromal cell (MSC)-based therapies, particularly adipose-derived MSCs, have gained increasing attention due to their immunomodulatory, anti-inflammatory, and metabolic regulatory properties demonstrated in preclinical models. Experimental studies suggest that MSCs influence adipose tissue remodeling, immune cell polarization, insulin sensitivity, and energy homeostasis predominantly through paracrine mechanisms, including the release of cytokines and extracellular vesicles, rather than long-term engraftment or differentiation. However, accumulating evidence indicates that obesity itself profoundly impairs endogenous MSC function through oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and epigenetic alterations, raising important concerns regarding the feasibility of autologous MSC-based approaches in obese individuals. Critically, no randomized controlled trial has evaluated MSC therapy for obesity with weight loss, body composition, or obesity-related clinical outcomes as primary endpoints; the available human evidence addresses glycemic control in type 2 diabetes and metabolic complications. In this review, we summarize current mechanistic insights, preclinical findings, and clinical data on MSC-based interventions for obesity-associated metabolic disorders, while critically discussing key biological, manufacturing, and regulatory challenges. Finally, we define the prerequisites for rational translation - standardized potency assays, obesity-specific early-phase trials with active comparators, objective body-composition endpoints, hemocompatibility testing, and long-term surveillance.
