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GLP‐2 receptor in the brainstem is required for glucose homeostasis and insulin sensitivity
Author(s) -
Shi Xuemei,
Chacko Shaji,
Brown Alexander,
Li Feng,
Guan Xinfu
Publication year - 2017
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.31.1_supplement.1040.7
Subject(s) - glucose homeostasis , medicine , endocrinology , brainstem , homeostasis , biology , insulin , glucagon , carbohydrate metabolism , receptor , insulin resistance
Background and Objective Glucagon‐like peptides (GLP‐1/2) are co‐secreted from enteroendocrine L cells in the gut and preproglucagon neurons in the brainstem, and are attributed through the gut‐brain axis to improving glucose homeostasis and insulin sensitivity after gastric bypass surgery. It is unknown if GLP‐2 receptor (GLP‐2R) in the brainstem plays a physiological role in glucose homeostasis. Our objective was to determine the physiological relevance of the brainstem GLP‐2R to glycemic control.Methods and Results 1) Generation of a brainstem‐specific Glp2r knockout mouse model: First, we revealed that GLP‐2R protein was localized to Phox2b neurons i n the brainstem dorsal vagal complex (DVC). Second, we generated Phox2b‐specific Glp2r knockout (PKO) mice by the Cre‐LoxP system, i.e., crossing Phox2b‐cre mice with Glp2r‐loxP‐flanked (floxed) mice. Third , we validated that Glp2r was deleted specifically in the DVC Phox2b neurons. 2) Characterization of the mouse metabolic phonotype: First, we showed that the PKO mice fed regular chow (~25 g BW) had higher blood glucose baseline after overnight fast, and lower blood glucose exclusion after ip glucose tolerance challenge. Second, we quantified glucose homeostasis and insulin sensitivity in conscious mice using hyperinsulinemic euglycemic clamp (coupled with dual stable isotopic tracers 6,6‐ 2 H 2 ‐d‐glucose and 2 H 2 O). The PKO mice at the basal condition had higher endogenous glucose production (5.10 ± 0.25 vs 8.02 ± 0.26 mmol/kg/h, respectively, for the WT and PKO mice). During hyperinsulinemic euglycemic clamp, the PKO mice had lower (−16%) glucose infusion rate (GIR) as resulted mainly from a decrease (−15%) in insulin‐mediated stimulation of peripheral glucose utilization ( R d). Conclusions Mice with Glp2r deletion in the brainstem DVC Phox2b neurons displayed hyperglycemia, glucose intolerance and insulin resistance, suggesting that the brainstem GLP‐2R plays an important, physiological role in the control of glucose homeostasis and insulin sensitivity. Support or Funding Information (Supported by the USDA CRIS grant 3092‐5001‐059 and the National NSFC grant 81570722).