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Research Article

Angptl4 links α-cell proliferation following glucagon receptor inhibition with adipose tissue triglyceride metabolism

Danny Ben-Zvi, Ornella Barrandon, Stephanie Hadley, Barak Blum, Quinn P. Peterson, and Douglas A. Melton
  1. Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138

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PNAS December 15, 2015 112 (50) 15498-15503; first published November 30, 2015; https://doi.org/10.1073/pnas.1513872112
Danny Ben-Zvi
Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138
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  • For correspondence: benzvi@fas.harvard.edu
Ornella Barrandon
Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138
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Stephanie Hadley
Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138
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Barak Blum
Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138
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Quinn P. Peterson
Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138
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Douglas A. Melton
Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138
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  1. Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved November 9, 2015 (received for review July 27, 2015)

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Significance

Hyperactivity of the hormone glucagon plays an important role in the pathophysiology of type 2 diabetes, but the factors that affect glucagon levels and α-cell proliferation are not entirely understood. This is particularly important for the development diabetes drugs based on glucagon receptor inhibition, which increase glucagon levels in plasma and α-cell mass. Here we show that increased levels of Angiopoietin-like 4 (Angptl4) in adipose tissue and plasma are sufficient to induce α-cell proliferation. Angptl4 is a conserved, secreted lipoprotein lipase inhibitor expressed by many tissues that is regulated by exercise and feeding. Moreover, Angptl4 is required for the compensatory hyperglucagonemia and α-cell proliferation following treatment with glucagon receptor antagonists.

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.

  • diabetes
  • metabolism
  • angiopoietin
  • glucagon
  • LPL

Footnotes

  • ↵1To whom correspondence should be addressed. Email: benzvi{at}fas.harvard.edu.
  • ↵2Present address: Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.

  • Author contributions: D.B.-Z., O.B., and D.A.M. designed research; D.B.-Z., O.B., and S.H. performed research; B.B. and Q.P.P. contributed new reagents/analytic tools; D.B.-Z. analyzed data; and D.B.-Z. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1513872112/-/DCSupplemental.

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Angptl4 induces α-cell proliferation
Danny Ben-Zvi, Ornella Barrandon, Stephanie Hadley, Barak Blum, Quinn P. Peterson, Douglas A. Melton
Proceedings of the National Academy of Sciences Dec 2015, 112 (50) 15498-15503; DOI: 10.1073/pnas.1513872112

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Angptl4 induces α-cell proliferation
Danny Ben-Zvi, Ornella Barrandon, Stephanie Hadley, Barak Blum, Quinn P. Peterson, Douglas A. Melton
Proceedings of the National Academy of Sciences Dec 2015, 112 (50) 15498-15503; DOI: 10.1073/pnas.1513872112
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