Author
SHI, XUEMEI - Children'S Nutrition Research Center (CNRC) | |
ZHOU, FUGUO - Children'S Nutrition Research Center (CNRC) | |
LI, XIAOJIE - Children'S Nutrition Research Center (CNRC) | |
CHANG, BENNY - Baylor College Of Medicine | |
LI, DEPEI - Md Anderson Cancer Center | |
WANG, YI - Children'S Nutrition Research Center (CNRC) | |
TONG, QINGCHUN - University Of Texas Health Science Center | |
XU, YONG - Children'S Nutrition Research Center (CNRC) | |
FUKUDA, MAKATO - Children'S Nutrition Research Center (CNRC) | |
ZHAO, JEAN - Harvard Medical School | |
LI, DELFI - China Agricultural University | |
Burrin, Douglas - Doug | |
CHAN, LAWRENCE - Baylor College Of Medicine | |
GUAN, XINFU - Children'S Nutrition Research Center (CNRC) |
Submitted to: Cell Metabolism
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 6/18/2013 Publication Date: 7/2/2013 Citation: Shi, X., Zhou, F., Li, X., Chang, B., Li, D., Wang, Y., Tong, Q., Xu, Y., Fukuda, M., Zhao, J.J., Li, D., Burrin, D.G., Chan, L., Guan, X. 2013. Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons. Cell Metabolism. 18:86-98. Interpretive Summary: The gut hormones glucagon-like peptides (namely GLP-1 and GLP-2) are key signals for the brain and pancreas to control energy homeostasis after a meal. However, it is unknown if the central nervous system (CNS) GLP-2 plays any physiological role in the control of feeding behavior. In this study, we demonstrate that mice lacking Glp2r in POMC neurons exhibit impaired energy balance (such as late-onset obesity, hyperphagic behavior, and food-seeking activity) and accelerated gastric emptying, whereas activation of GLP-2R signaling in the brain suppresses food intake and gastric emptying through the MC4R signaling pathway. Thus, Glp2r in POMC neurons is essential for the physiological short-term control of feeding behavior (such as meal frequency and gastric emptying), which contributes to the homeostatic long-term control of energy balance and body weight. Moreover, gastric emptying is a key process for the short-term control of feeding behavior (satiation and satiety), and POMC neuron-mediated suppression of food intake may be executed through decelerating gastric emptying. Therefore, this study suggests that CNS GLP-2 is a key satiety signal for the physiological short-term control of feeding behavior and gastric motility and contributes to the homeostatic long-term control of energy balance and body weight. Thus, GLP-2R activation in POMC neurons is essential for the maintenance of energy balance and glucose homeostasis. Technical 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 Alpha 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 Alpha Knock-out 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. |