Potential role of postbiotics in supporting lean mass preservation and weight-loss sustainability during GLP-1-based anti-obesity therapy.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped obesity management by producing clinically meaningful weight loss, primarily through appetite suppression and reduced energy intake. However, rapid pharmacologically induced weight loss may be accompanied by unfavorable body-composition changes, including reductions in lean mass, and weight regain is common following treatment discontinuation, underscoring a major durability gap. Although preclinical studies link GLP-1 signaling to brown adipose tissue (BAT) activation and adipose tissue browning, human data indicate that BAT mass and thermogenic capacity in adulthood-particularly in obesity-are limited, constraining the contribution of energy expenditure to sustained weight loss. Beyond pharmacotherapy, emerging evidence suggests that gut microbiota-derived metabolites and postbiotics, such as short-chain fatty acids (SCFAs) and tryptophan-derived indoles, can modulate enteroendocrine function, inflammatory tone, insulin sensitivity, and gut-brain communication. While postbiotics are unlikely to replicate the magnitude of weight loss achieved with GLP-1RAs, their continuous, physiology-aligned mode of action positions them as biologically plausible adjuncts that may support weight-loss sustainability and improve the metabolic context for lean mass preservation. This mini-review integrates pharmacological, physiological, and nutritional perspectives to examine the mechanisms underlying GLP-1-induced weight loss and the physiological limits of thermogenic pathways in humans. It further discusses the potential complementary role of postbiotics within convergence-based strategies aimed at preserving lean mass and enhancing long-term obesity management.