POMC‐GLP‐2R signaling and action in the control of feeding behavior and gastric motility

Abstract

Glucagon‐like peptides (GLP‐1/2) are released in response to food intake. Central infusion of GLP‐2 suppresses food intake and gastric motility, and this is supposedly mediated through its receptor (GLP‐2R) action in the brain. However, the physiological relevance of GLP‐2R in the brain is unknown. Thus, our aims were to determine if GLP‐2R in POMC neurons regulates feeding behavior and gastric motility. [1] We generated mice with Glp2r deletion in POMC neurons, which showed late‐onset obesity, higher food intake, increased meal frequency, and accelerated gastric emptying using 13C‐octanoic acid breath test. For liquid meal, half‐excretion time was 29.0 ± 4.5 and 51.2 ± 4.5 min; and lag phase 17.8 ± 3.0 and 31.5 ± 3.0 min for the KO and WT mice, respectively. [2] We generated POMC‐specific p110α knockout mice and POMC‐specific FoxO1‐GFP over‐expression mice to define cellular mechanisms underlying GLP‐2‐initiated anorexic action. Using immunoprecipitation, we found that GLP‐2R interacted with p85α in hippocampal neurons. GLP‐2 acutely induced GLP‐2R translocation from membrane to cytoplasm, and enhanced Akt phosphorylation in a PI3K‐dependent manner. Moreover, GLP‐2 (at 20 nM for 30 min) induced nuclear exclusion of FoxO1‐GFP in POMC neurons, and this effect was abolished in POMC‐specific p110α KO mice, suggesting that GLP‐2 may disinhibit expression of FoxO1‐targeted genes in POMC neurons. Furthermore, GLP‐2 differentially modulated excitation of functionally‐segregated POMC neurons in a PI3K‐dependent manner. In conclusion, Glp2r deletion in POMC neurons impairs feeding behavior and gastric motility; and GLP‐2 acutely activates the PI3K signaling pathway in POMC neurons to modulate neuronal excitation and gene expression. Therefore, CNS GLP‐2R plays an important, physiological role in the control of food intake and gastric emptying.