Glucagon‐Like Peptide‐1 Links Ingestion, Homeostasis, and the Heart

Glucagon‐like peptide‐1 (GLP‐1), a hormone released from enteroendocrine cells in the distal small and large intestines in response to nutrients and other stimuli, not only controls eating and insulin release, but is also involved in drinking control as well as renal and cardiovascular functions. Moreover, GLP‐1 functions as a central nervous system peptide transmitter, produced by preproglucagon (PPG) neurons in the hindbrain. Intestinal GLP‐1 inhibits eating by activating vagal sensory neurons directly, via GLP‐1 receptors (GLP‐1Rs), but presumably also indirectly, by triggering the release of serotonin from enterochromaffin cells. GLP‐1 enhances glucose‐dependent insulin release via a vago‐vagal reflex and by direct action on beta cells. Finally, intestinal GLP‐1 acts on the kidneys to modulate electrolyte and water movements, and on the heart, where it provides numerous benefits, including anti‐inflammatory, antiatherogenic, and vasodilatory effects, as well as protection against ischemia/reperfusion injury and arrhythmias. Hindbrain PPG neurons receive multiple inputs and project to many GLP‐1R‐expressing brain areas involved in reward, autonomic functions, and stress. PPG neuron‐derived GLP‐1 is involved in the termination of large meals and is implicated in the inhibition of water intake. This review details GLP‐1's roles in these interconnected systems, highlighting recent findings and unresolved issues, and integrating them to discuss the physiological and pathological relevance of endogenous GLP‐1 in coordinating these functions. As eating poses significant threats to metabolic, fluid, and immune homeostasis, the body needs mechanisms to mitigate these challenges while sustaining essential nutrient intake. Endogenous GLP‐1 plays a crucial role in this “ingestive homeostasis.”