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.
Authors
- Xuejiao Tang
- Mengliu Yang (ORCID: https://orcid.org/0000-0003-1896-0002)
- Shan Geng (ORCID: https://orcid.org/0000-0003-0838-4726)
- Shiyao Xue (ORCID: https://orcid.org/0000-0001-6459-8871)
- Hongting Zheng (ORCID: https://orcid.org/0000-0002-6930-0103)
- Dongfang Liu (ORCID: https://orcid.org/0000-0002-8801-2190)
- Zhiming Zhu (ORCID: https://orcid.org/0000-0003-1035-5588)
- Ke Li (ORCID: https://orcid.org/0000-0003-0935-6567)
- Gangyi Yang (ORCID: https://orcid.org/0000-0002-6458-6747)
- Chen Chen (ORCID: https://orcid.org/0000-0003-2104-534X)
- Ling Li (ORCID: https://orcid.org/0000-0002-0087-3034)
- Yuanqiang Wang (ORCID: https://orcid.org/0000-0002-3024-2866)
- Shan Yang (ORCID: https://orcid.org/0000-0003-0583-3637)
Institutions
- Army Medical University (CN)
- The University of Queensland (AU)
- Dalian Medical University (CN)
- Daping Hospital (CN)
- Second Affiliated Hospital of Chongqing Medical University (CN)
- Xinqiao Hospital (CN)
- Chongqing University of Technology (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1038/s44318-024-00300-4
- Citations
- 5
- Primary Topic
- Regulation of Appetite and Obesity
- Type
- article
- Field-Weighted Citation Impact
- 1.37
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Chongqing Science and Technology Commission
- Chongqing Medical University
- Natural Science Foundation of Chongqing
- Chongqing Municipal Education Commission
- Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission