Open AccessGlucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis
Author(s) -
Rachel J. Perry,
Dongyan Zhang,
Mateus T. Guerra,
Allison L. Brill,
Leigh Goedeke,
Ali Nasiri,
Aviva Rabin-Court,
Yong Liang Wang,
Liang Peng,
Sylvie Dufour,
Ye Zhang,
XianMan Zhang,
Gina M. Butrico,
Keshia Toussaint,
Yuichi Nozaki,
Gary W. Cline,
Kitt Falk Petersen,
Michael H. Nathanson,
Barbara E. Ehrlich,
Gerald I. Shulman
Publication year - 2020
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-020-2074-6
Subject(s) - medicine , endocrinology , lipolysis , glucagon , gluconeogenesis , steatosis , beta oxidation , lipogenesis , insulin resistance , insulin , biology , chemistry , lipid metabolism , adipose tissue , metabolism
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 diabetes 1-3 , 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.