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.