Location: Children's Nutrition Research CenterTitle: GLP-2 receptor deficiency in the mouse brain impairs glucose homeostasis) Author
Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Abstract Only
Publication Acceptance Date: 1/25/2011
Publication Date: 4/1/2011
Citation: Shi, X., Li, X., Wang, Y., Li, D., Chang, B., Chan, L., Guan, X. 2011. GLP-2 receptor deficiency in the mouse brain impairs glucose homeostasis [Abstract]. Federation of American Societies for Experimental Biology Conference. 25:1062.14. Interpretive Summary:
Technical Abstract: In response to food intake, glucagon-like peptide-2 (GLP-2) with GLP-1 is co-secreted from enteroendocrine L cells in the gut. GLP-2 receptor (GLP-2R) is expressed in the hypothalamus, a key tissue to integrate energy signals to regulate energy balance and glucose homeostasis. However, the physiological role of brain GLP-2R has not been defined. Our objective was to critically test if brain GLP-2R activation is essential for glucose homeostasis.  We found that icv infusion of GLP-2 increased glucose tolerance with increased expression of POMC gene in the hypothalamus.  We showed that GLP-2 (100 nM) increased firing rate by 79%, but decreased membrane potential (Control: –38.4 +/- 2.2 vs GLP-2: –32.1 +/- 1.9 mV) of POMC neurons on hypothalamic slices using the whole-cell patch clamp.  Using our newly generated POMC-specific glp2r knockout (CKO) mice, we demonstrated that glucose intolerance increased by 42% in the CKO mice. Moreover, glucose infusion rate decreased in the CKO mice during hyperinsulinemic euglycemic clamp (WT: 6.46 +/- 0.27 vs CKO: 4.54 +/- 0.24 mmol/kg/h). During the clamp, hepatic glucose production increased (WT: 3.54 +/- 0.34 vs CKO: 4.30 +/- 0.35 mmol/kg/h) with increased fraction of gluconeogenesis by 47% and mRNA abundance of G6Pase & PEPCK by 200% in the CKO mice. We conclude that GLP-2R deficiency in POMC neurons impairs glucose homeostasis by decreasing insulin sensitivity, suggesting that brain GLP-2R activation is important for maintenance of glucose homeostasis at high postprandial insulin.