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United States Department of Agriculture

Agricultural Research Service

Research Project: MOLECULAR, CELLULAR, AND REGULATORY ASPECTS OF OBESITY DEVELOPMENT IN CHILDREN

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Title: GLP-2 receptor deficiency in the mouse brain impairs glucose homeostasis)

Author
item Shi, Xuemei
item Li, Xiaojie
item Wang, Yi
item Li, Depei
item Chang, Benny
item Chan, Lawrence
item Guan, Xinfu

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. [1] We found that icv infusion of GLP-2 increased glucose tolerance with increased expression of POMC gene in the hypothalamus. [2] 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. [3] 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.

Last Modified: 8/24/2016
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