Endocrine Regulation of Appetite: Interactions between Gut Microbiota, Microbial Metabolites, and Appetite-related...

The gut microbiota has emerged as a key endocrine modulator that shapes host appetite regulation through its metabolites and their interactions with enteroendocrine and central neuroendocrine pathways. Microbial metabolites-including short-chain fatty acids, bile acid derivatives, indole compounds, and tryptophan-derived serotonin-activate receptors such as G-protein-coupled receptor 41/43, Takeda G protein-coupled receptor 5, and Toll-like receptor 4 on enteroendocrine cells, influence the secretion of appetite-related hormones including ghrelin, leptin, glucagon-like peptide-1, peptide YY, nesfatin-1, and cholecystokinin. These hormones subsequently modulate hypothalamic circuits, particularly the NPY/AgRP and POMC/CART pathways, establishing a mechanistic link between microbial signaling and central appetite control. Ghrelin serves as the primary orexigenic hormone, whereas leptin, glucagon-like peptide-1, peptide YY, nesfatin-1, and cholecystokinin collectively exert anorexigenic effects that promote satiety and energy homeostasis. Dysbiosis disrupts receptor-mediated endocrine signaling, alters hormonal secretion, and contributes to leptin resistance, impaired glucagon-like peptide-1 responsiveness, and dysregulated appetite-key features in obesity, insulin resistance, and metabolic syndrome. This review synthesizes current mechanistic insights into the microbiota-hormone axis and highlights how microbial modulation influences endocrine appetite regulation. Understanding these interactions provides a translational framework for developing microbiota-targeted endocrine therapies aimed at restoring metabolic balance and preventing obesity and related metabolic disorders.