GLP‐2 reprograms glucose metabolism in intestinal stem cells

Abstract

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-13C-d-glucose tracer and BrdU incorporation. The mouse undifferentiating mini-guts were treated with GLP-2 (100 nM) ± glycolysis inhibitor and labeled with U-13C-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 13C 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.