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GLP‐2 receptor deficiency in the mouse brain impairs glucose homeostasis
Author(s) -
Shi Xuemei,
Li Xiaojie,
Wang Yi,
Li Depei,
Chang Benny,
Chan Lawrence,
Guan Xinfu
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1062.14
Subject(s) - medicine , endocrinology , glucose homeostasis , homeostasis , proglucagon , energy homeostasis , gluconeogenesis , glucagon like peptide 1 , hypothalamus , glucagon , receptor , biology , chemistry , enteroendocrine cell , insulin , type 2 diabetes , metabolism , insulin resistance , endocrine system , diabetes mellitus , hormone
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.