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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-p85? 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-p110? 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.

SUBMITTER: Shi X 

PROVIDER: S-EPMC3752162 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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

Shi Xuemei X   Zhou Fuguo F   Li Xiaojie X   Chang Benny B   Li Depei D   Wang Yi Y   Tong Qingchun Q   Xu Yong Y   Fukuda Makoto M   Zhao Jean J JJ   Li Defa D   Burrin Douglas G DG   Chan Lawrence L   Guan Xinfu X  

Cell metabolism 20130701 1

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-media  ...[more]

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