Gut hormones beyond the gut: enteroendocrine control of systemic metabolism

Abstract

Gut enteroendocrine cells (EECs) sense luminal cues and secrete more than 20 hormones that orchestrate physiological responses across multiple organ systems. Beyond their established roles in gastrointestinal (GI) regulation, EECs and their hormones are integral regulators of systemic metabolism. Dysregulated metabolic states can profoundly alter EEC subpopulation and secretion profile, and these changes further contribute to pathologies in various tissues including the liver, pancreas, adipose tissue, and the cardiovascular system. Importantly, gut hormone-based therapies, such as glucagon-like peptide‑1 (GLP-1) receptor agonists, have achieved remarkable success in obesity and diabetes treatment, and emerging evidence supports their potential applications in nonalcoholic steatohepatitis, atherosclerosis, and other metabolic diseases. In this review, we highlight the expanding roles of EECs in extraintestinal metabolic regulation, examine how diet and disease reshape EEC function, and discuss the translational opportunities of targeting gut hormone pathways for the treatment of metabolic disorders.