Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis
Authors: Yongliang Wang
Xian-Man Zhang
Allison L Brill
Sylvie Dufour
Ye Zhang
Gina M Butrico
Rachel J Perry
Kitt Falk Petersen
Keshia Toussaint
Leigh Goedeke
Liang Peng
Yuichi Nozaki
Aviva Rabin-Court
Gary W Cline
Barbara E Ehrlich
Michael H Nathanson
Ali R Nasiri
Mateus T Guerra
Dongyan Zhang
Gerald I Shulman
Journal: Nature (2020)
Discipline: Multidisciplinary
Keywords: insulin; glucagon; hepatic glucose metabolism; type-2 diabetes; hepatic gluconeogenesis
Affiliations: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA., Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA., Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA., Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. ., Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA. .

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. 

Retracted: No

PubPeer comments:
 (a) In the introduction section, the authors defined a function $x$ as $$x: S(n) to [0,1]$$ where $$S(n) ={1,2, ldots, n}$$ Then, the authors denoted $X^{ n }$ the set of all such functions and defined u201can aggregation operator (of dimension $n$)u201d is a bounded and monotonic function $A$ as $$A: X^{ n } to [0,1]$$ which satisfying the first condition that $$A((0, ldots, 0)) = 0quad text{and}quad A((1, ldots, 1)) = 1$$ and the second condition that for any $$x,yin X^{ n } quad text{with}quad xle y$$ $$A(x)le A(y)$$ Such a definition is so puzzling because the notations $$A((0, ldots, 0)) = 0quad text{and}quad A((1, ldots, 1)) = 1$$ are not interpretable in this context. (b) The authors claimed that the induced ordered weighted averaging operator IOWA introduced in the paper (DOI: 10.1109 3477.752789) has been already been successfully applied to numerical applications. The authors also pointed out that a drawback of non-uniqueness caused by tied values. However, this is just a minor issue related to the IOWA operator. As pointed out in the comment on https: pubpeer.com publications DDFBBFDB6C9D1729F151E364F074DA the IOWA operator is conceptually flawed. If the vector for rearranging the weights is not fixed, the corresponding IOWA operator is not monotonic and hence not qualified as an aggregation operator. If the vector for rearranging the weights is fixed, the corresponding IOWA operator is nothing but the weighted averaging operator after rearranging the weights.  (c) In Definition 4, the authors presented the definition of an induced ordered weighted averaging operator in a slightly different form compared to its original version of Ref[11]. According to Definition 4, it is clear that the u201cinducing functionu201d $$t: S(n) to [0,1]$$ is given, that is, **is fixed**. This means that the weights in the vector $w$ may be rearranged according to the inverse of the permutation $sigma$ induced by $t$. As a consequence, the IOWA operator defined by eq.(6) is simply a **weighted averaging operator** no matter whether or not it is called an induced ordered weighted averaging operator.  ,