Intestinal NUCB2/nesfatin-1 regulates hepatic glucose production via the MC4R-cAMP-GLP-1 pathway

Communication of gut hormones with the central nervous system is important to regulate systemic glucose homeostasis, but the precise underlying mechanism involved remain little understood. Nesfatin-1, encoded by nucleobindin-2 (NUCB2), a potent anorexigenic peptide hormone, was found to be released from the gastrointestinal tract, but its specific function in this context remains unclear. Herein, we found that gut nesfatin-1 can sense nutrients such as glucose and lipids and subsequently decreases hepatic glucose production. Nesfatin-1 infusion in the small intestine of NUCB2-knockout rats reduced hepatic glucose production via a gut - brain - liver circuit. Mechanistically, NUCB2/nesfatin-1 interacted directly with melanocortin 4 receptor (MC4R) through its H-F-R domain and increased cyclic adenosine monophosphate (cAMP) levels and glucagon-like peptide 1 (GLP-1) secretion in the intestinal epithelium, thus inhibiting hepatic glucose production. The intestinal nesfatin-1 -MC4R-cAMP-GLP-1 pathway and systemic gut-brain communication are required for nesfatin-1 - mediated regulation of liver energy metabolism. These findings reveal a novel mechanism of hepatic glucose production control by gut hormones through the central nervous system. The role of peptide hormone nesfatin-1 (encoded by the NUCB2 gene) in regulating systemic nutrient sensing and metabolism remains unclear. This study reveals a function for intestinal nesfatin-1 in controlling hepatic glucose production and insulin sensitivity via a gut-brain-liver circuit.Nesfatin-1 infusion in the upper small intestine improves hepatic glucose metabolism and insulin sensitivity in NUCB2 KO rats.Nesfatin-1 interacts with the melanocortin 4 receptor (MC4R) to activate cAMP - GLP-1 signaling, resulting in reduced hepatic glucose production.Intestinal NUCB2/nesfatin-1 regulates hepatic glucose production in a neurotransmission-dependent manner. Peptide hormone nesfatin-1 couples intestinal nutrient sensing to liver glucose generation via a gut-brain-liver circuit.