Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis

Rachel J. Perry, Dongyan Zhang, Mateus T. Guerra, Allison L. Brill, Leigh Goedeke, Ali R. Nasiri, Aviva Rabin-Court, Yongliang Wang, Liang Peng, Sylvie Dufour, Ye Zhang, Xian-Man Zhang, Gina M. Butrico, Keshia Toussaint, Yuichi Nozaki, Gary W. Cline, Kitt Falk Petersen, Michael H. Nathanson, Barbara E. Ehrlich and Gerald I. Shulman ()
Additional contact information
Rachel J. Perry: Yale School of Medicine
Dongyan Zhang: Yale School of Medicine
Mateus T. Guerra: Yale School of Medicine
Allison L. Brill: Yale School of Medicine
Leigh Goedeke: Yale School of Medicine
Ali R. Nasiri: Yale School of Medicine
Aviva Rabin-Court: Yale School of Medicine
Yongliang Wang: Yale School of Medicine
Liang Peng: Yale School of Medicine
Sylvie Dufour: Yale School of Medicine
Ye Zhang: Yale School of Medicine
Xian-Man Zhang: Yale School of Medicine
Gina M. Butrico: Yale School of Medicine
Keshia Toussaint: Yale School of Medicine
Yuichi Nozaki: Yale School of Medicine
Gary W. Cline: Yale School of Medicine
Kitt Falk Petersen: Yale School of Medicine
Michael H. Nathanson: Yale School of Medicine
Barbara E. Ehrlich: Yale School of Medicine
Gerald I. Shulman: Yale School of Medicine

Nature, 2020, vol. 579, issue 7798, 279-283

Abstract: Abstract Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes1–3, the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation—all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment—reversing hepatic steatosis and glucose intolerance—were abrogated in Insp3r1 (also known as Itpr1)-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2074-6 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:579:y:2020:i:7798:d:10.1038_s41586-020-2074-6

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2074-6

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().