Central GLP-2 Enhances Hepatic Insulin Sensitivity via Activating PI3K Signaling in POMC Neurons

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. [Display omitted] •GLP-2R in POMC neurons is required for GLP-2 to promote glucose homeostasis•GLP-2 modulates excitability of POMC neurons in GLP-2R- and PI3K-dependent manners•GLP-2 activates GLP-2R-PI3K-FoxO1 signaling pathway in POMC neurons•Central GLP-2 enhances hepatic insulin sensitivity in a PI3K-dependent manner