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Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved November 9, 2015 (received for review July 27, 2015)
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.
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.
Angptl4 induces α-cell proliferation
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- Biological Sciences
- Physiology
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