Intestinal NUCB2/nesfatin-1 regulates hepatic glucose production via the MC4R-cAMP-GLP-1 pathway
- EMBO J. 2025 Jan;44(1):54-74. doi: 10.1038/s44318-024-00300-4.
- 1. Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
- 2. Endocrinology, SBMS, Faculty of Medicine, University of Queensland, Brisbane, QLD, 4072, Australia.
- 3. Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
- 4. Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
- 5. School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China.
- 6. Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. [email protected].
- 7. The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China. [email protected].
- 8. Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. [email protected].
- # Contributed equally.
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.