Glucagon-like peptide-1 reduces pancreatic β-cell mass through hypothalamic neural pathways in high-fat diet-induced obese rats

• Published in: Scientific reports Vol. 7; no. 1; pp. 5578 - 11
• Main Authors: Ando, Hisae, Gotoh, Koro, Fujiwara, Kansuke, Anai, Manabu, Chiba, Seiichi, Masaki, Takayuki, Kakuma, Tetsuya, Shibata, Hirotaka
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 17.07.2017; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; c-Fos protein; Cell Proliferation - drug effects; Cell Size - drug effects; Central nervous system; Diet, High-Fat - adverse effects; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - administration & dosage; Glucagon-Like Peptide 1 - pharmacology; Glucose; Glucose - metabolism; Glucose Intolerance - drug therapy; Glucose Intolerance - etiology; Glucose tolerance; High fat diet; Hyperplasia; Hypothalamus; Hypothalamus - drug effects; Hypothalamus - metabolism; Injections, Intraperitoneal; Insulin; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Intolerance; Liraglutide - administration & dosage; Liraglutide - pharmacology; Neural Pathways - drug effects; Obesity; Obesity - chemically induced; Obesity - drug therapy; Obesity - metabolism; Pancreas; Proto-Oncogene Proteins c-fos - metabolism; Rats; Rats, Sprague-Dawley; Rodents; Sensory neurons; Sympathectomy; Sympathetic nervous system; Vagotomy
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-05371-4

We examined whether glucagon-like peptide-1 (GLP-1) affects β-cell mass and proliferation through neural pathways, from hepatic afferent nerves to pancreatic efferent nerves via the central nervous system, in high-fat diet (HFD)-induced obese rats. The effects of chronic administration of GLP-1 (7-36) and liraglutide, a GLP-1 receptor agonist, on pancreatic morphological alterations, c-fos expression and brain-derived neurotrophic factor (BDNF) content in the hypothalamus, and glucose metabolism were investigated in HFD-induced obese rats that underwent hepatic afferent vagotomy (VgX) and/or pancreatic efferent sympathectomy (SpX). Chronic GLP-1 (7-36) administration to HFD-induced obese rats elevated c-fos expression and BDNF content in the hypothalamus, followed by a reduction in pancreatic β-cell hyperplasia and insulin content, thus resulting in improved glucose tolerance. These responses were abolished by VgX and SpX. Moreover, administration of liraglutide similarly activated the hypothalamic neural pathways, thus resulting in a more profound amelioration of glucose tolerance than native GLP-1 (7-36). These data suggest that GLP-1 normalizes the obesity-induced compensatory increase in β-cell mass and glucose intolerance through a neuronal relay system consisting of hepatic afferent nerves, the hypothalamus, and pancreatic efferent nerves.