title: Angptl4 links α-cell proliferation following glucagon receptor inhibition with adipose tissue triglyceride metabolism.
abstract: Type 2 diabetes is characterized by a reduction in insulin function and an increase in glucagon activity that together result in hyperglycemia. Glucagon receptor antagonists have been developed as drugs for diabetes; however, they often increase glucagon plasma levels and induce the proliferation of glucagon-secreting α-cells. We find that the secreted protein Angiopoietin-like 4 (Angptl4) is up-regulated via Pparγ activation in white adipose tissue and plasma following an acute treatment with a glucagon receptor antagonist. Induction of adipose angptl4 and Angptl4 supplementation promote α-cell proliferation specifically. Finally, glucagon receptor antagonist improves glycemia in diet-induced obese angptl4 knockout mice without increasing glucagon levels or α-cell proliferation, underscoring the importance of this protein. Overall, we demonstrate that triglyceride metabolism in adipose tissue regulates α-cells in the endocrine pancreas.
authors.affiliation: Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 benzvi@fas.harvard.edu.
authors.forename: Danny
authors.initials: D
authors.lastname: Ben-Zvi
authors.affiliation: Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138.
authors.forename: Ornella
authors.initials: O
authors.lastname: Barrandon
authors.affiliation: Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hadley
authors.affiliation: Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138.
authors.forename: Barak
authors.initials: B
authors.lastname: Blum
authors.affiliation: Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138.
authors.forename: Quinn P
authors.initials: QP
authors.lastname: Peterson
authors.affiliation: Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Melton
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000097:blood / Q000378:metabolism*; D000818:Animals; D031204:Caloric Restriction; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D005934:Glucagon / Q000097:blood; D050416:Glucagon-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D047495:PPAR gamma; D018027:Receptors, Glucagon; D014280:Triglycerides; D005934:Glucagon
keywords: LPL; angiopoietin; diabetes; glucagon; metabolism