Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons.

Abstract

Glucagon-like peptides (GLP-1/GLP-2) are coproduced and highlighted as key modulators to improve glucose homeostasis and insulin sensitivity after bariatric surgery. However, it is unknown if CNS GLP-2 plays any physiological role in the control of glucose homeostasis and insulin sensitivity. We show that mice lacking GLP-2 receptor (GLP-2R) in POMC neurons display glucose intolerance and hepatic insulin resistance. GLP-2R activation in POMC neurons is required for GLP-2 to enhance insulin-mediated suppression of hepatic glucose production (HGP) and gluconeogenesis. GLP-2 directly modulates excitability of POMC neurons in GLP-2R- and PI3K-dependent manners. GLP-2 initiates GLP-2R-p85α interaction and facilitates PI3K-Akt-dependent FoxO1 nuclear exclusion in POMC neurons. Central GLP-2 suppresses basal HGP and enhances insulin sensitivity, which are abolished in POMC-p110α KO mice. Thus, CNS GLP-2 plays a key physiological role in the control of HGP through activating PI3K-dependent modulation of membrane excitability and nuclear transcription of POMC neurons in the brain.

• Authors: Xuemei Shi, Fuguo Zhou, Xiaojie Li, Benny Chang, Depei Li, Yi Wang, Qingchun Tong, Yong Xu, Makoto Fukuda, Jean J Zhao, Defa Li, Douglas G Burrin, Lawrence Chan, Xinfu Guan
• Journal: Cell metabolism (Cell Metab) Vol. 18 Issue 1 Pg. 86-98 (Jul 02 2013) ISSN: 1932-7420 [Electronic] United States
• PMID: 23823479 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Foxo1 protein, mouse
• Glucagon-Like Peptide 2
• Glucagon-Like Peptide-2 Receptor
• Receptors, Glucagon
• Pro-Opiomelanocortin
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Glucose

Topics

• Animals
• Cells, Cultured
• Forkhead Box Protein O1
• Forkhead Transcription Factors (physiology)
• Glucagon-Like Peptide 2 (physiology)
• Glucagon-Like Peptide-2 Receptor
• Glucose (metabolism)
• Homeostasis (physiology)
• Insulin Resistance (physiology)
• Liver (physiology)
• Male
• Mice
• Mice, Inbred Strains
• Mice, Knockout
• Models, Animal
• Neurons (cytology, physiology)
• Phosphatidylinositol 3-Kinases (physiology)
• Pro-Opiomelanocortin (deficiency, genetics, physiology)
• Proto-Oncogene Proteins c-akt (physiology)
• Receptors, Glucagon (deficiency, genetics, physiology)
• Signal Transduction (physiology)