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

Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):15498-503. doi: 10.1073/pnas.1513872112. Epub 2015 Nov 30.

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.

Keywords: LPL; angiopoietin; diabetes; glucagon; metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism*
  • Angiopoietin-Like Protein 4
  • Angiopoietins / blood
  • Angiopoietins / metabolism*
  • Animals
  • Caloric Restriction
  • Cell Proliferation
  • Gene Expression Regulation
  • Glucagon / blood
  • Glucagon-Secreting Cells / cytology*
  • Glucagon-Secreting Cells / metabolism*
  • Mice, Inbred C57BL
  • Mice, SCID
  • PPAR gamma / agonists
  • PPAR gamma / metabolism
  • Receptors, Glucagon / antagonists & inhibitors*
  • Receptors, Glucagon / metabolism
  • Triglycerides / metabolism*

Substances

  • Angiopoietin-Like Protein 4
  • Angiopoietins
  • Angptl4 protein, mouse
  • PPAR gamma
  • Receptors, Glucagon
  • Triglycerides
  • Glucagon