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GLP‐2 reprograms glucose metabolism in intestinal stem cells
Author(s) -
Shi Xuemei,
Alves Tiago,
Zeng XiLei,
Kibbey Richard,
Estes Mary,
Guan Xinfu
Publication year - 2015
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.29.1_supplement.851.4
Subject(s) - anaerobic glycolysis , glycolysis , biology , cell growth , microbiology and biotechnology , biochemistry , reprogramming , metabolic pathway , stem cell , warburg effect , carbohydrate metabolism , metabolism , cell
Glucagon‐like peptide 2 (GLP‐2) is an enterotrophic peptide to enhance intestinal crypt cell proliferation. However, cellular mechanisms underlying its tropic action are still unclear. Using the innovative mouse mini‐guts models, we wanted to determine if GLP‐2 directly modulates metabolic reprogramming (aerobic glycolysis) and cellular function (proliferation) in the intestinal stem cells. Intracellular metabolic fluxes and cell proliferation in the mouse mini‐guts were quantified by U‐ 13 C‐d‐glucose tracer and BrdU incorporation. The mouse undifferentiating mini‐guts were treated with GLP‐2 (100 nM) ± glycolysis inhibitor and labeled with U‐ 13 C‐d‐glucose tracer or BrdU for 90~120 min. We show that the GLP‐2 receptor (GLP‐2R) was required for the growth of mouse mini‐guts; and for GLP‐2 to augment cell proliferation in an aerobic glycolysis‐dependent manner. Using LC‐MS/MS‐based metabolomics, moreover, we revealed that GLP‐2 shifted 13 C metabolic fluxes to aerobic glycolysis and de novo biosynthesis of glutamate in the mini‐guts, and this metabolic reprogramming was negated by glycolysis inhibition. These data suggest that via the metabolic reprogramming of glucose, GLP‐2 channels glycolytic intermediates for amino acid biosynthesis to support cell proliferation. Furthermore, we identified that GLP‐2 acutely induced phosphorylation and nuclear translocation of pyruvate kinase M2 in the mini‐guts. We conclude that GLP‐2 plays a novel role in metabolic reprogramming of glucose for biosynthesis to support cell proliferation in the crypt stem cells.