GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7.
Glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L cells promotes nutrient disposal via the incretin effect. However, the majority of L cells are localized to the distal gut, suggesting additional biological roles for GLP-1. Here, we demonstrate that GLP-1 receptor (GLP-1R) signaling controls mucosal expansion of the small bowel (SB) and colon. These actions did not require the epidermal growth factor (EGF) or intestinal epithelial insulin-like growth factor (IGF1) receptors but were absent in Glp1r(-/-) mice. Polyp number and size were increased in SB of exendin-4-treated Apc(Min/+) mice, whereas polyp number was reduced in SB and colon of Glp1r(-/-):Apc(Min/+) mice. Exendin-4 increased fibroblast growth factor 7 (Fgf7) expression in colonic polyps of Apc(Min/+) mice and failed to increase intestinal growth in mice lacking Fgf7. Exogenous exendin-4 and Fgf7 regulated an overlapping set of genes important for intestinal growth. Thus, gain and loss of GLP-1R signaling regulates gut growth and intestinal tumorigenesis.
Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada.
Jacqueline A
JA
Koehler
Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada.
Laurie L
LL
Baggio
Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada.
Bernardo
B
Yusta
Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada.
Christine
C
Longuet
Department of Physiology, University of Toronto, Toronto, ON M5S1A8, Canada.
Katherine J
KJ
Rowland
Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada.
Xiemin
X
Cao
Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada.
Dianne
D
Holland
Department of Physiology, University of Toronto, Toronto, ON M5S1A8, Canada.
Patricia L
PL
Brubaker
Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada. Electronic address: drucker@lunenfeld.ca.
Daniel J
DJ
Drucker
D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D003106:Colon / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D004815:Epidermal Growth Factor / Q000378:metabolism; D000077270:Exenatide; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D054795:Incretins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014688:Venoms / Q000378:metabolism; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
C496454:Fgf7 protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D010455:Peptides; D014688:Venoms; D051523:Fibroblast Growth Factor 7; D004815:Epidermal Growth Factor; D000077270:Exenatide; D017526:Receptor, IGF Type 1; D000097789:Glucagon-Like Peptide-1 Receptor Agonists