Increasing hepatic glycogen moderates the diabetic phenotype in insulin-deficient Akita mice.

Content Provider	Europe PMC
Author	López-Soldado, Iliana Guinovart, Joan J. Duran, Jordi
Copyright Year	2021
Abstract	Hepatic glycogen metabolism is impaired in diabetes. We previously demonstrated that strategies to increase liver glycogen content in a high-fat-diet mouse model of obesity and insulin resistance led to a reduction in food intake and ameliorated obesity and glucose tolerance. These effects were accompanied by a decrease in insulin levels, but whether this decrease contributed to the phenotype observed in this animal was unclear. Here we sought to evaluate this aspect directly, by examining the long-term effects of increasing liver glycogen in an animal model of insulin-deficient and monogenic diabetes, namely the Akita mouse, which is characterized by reduced insulin production. We crossed Akita mice with animals overexpressing protein targeting to glycogen (PTG) in the liver to generate Akita mice with increased liver glycogen content (Akita-PTGOE). Akita-PTGOE animals showed lower glycemia, lower food intake, and decreased water consumption and urine output compared with Akita mice. Furthermore, Akita-PTGOE mice showed a restoration of the hepatic energy state and a normalization of gluconeogenesis and glycolysis back to nondiabetic levels. Moreover, hepatic lipogenesis, which is reduced in Akita mice, was reverted in Akita-PTGOE animals. These results demonstrate that strategies to increase liver glycogen content lead to the long-term reduction of the diabetic phenotype, independently of circulating insulin.
ISSN	00219258
Volume Number	296
PubMed Central reference number	PMC8027280
PubMed reference number	33667544
Journal	The Journal of Biological Chemistry [J. Biol. Chem]
e-ISSN	1083351X
DOI	10.1016/j.jbc.2021.100498
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2021-01-01
Access Restriction	Open
Rights License	This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). © 2021 The Authors
Subject Keyword	glycogen glucose protein targeting to glycogen (PTG) liver diabetes Akita ATP glycolysis gluconeogenesis insulin ATGL, adipose triglyceride lipase FAS, fatty acid synthase FFA, free fatty acid GK, glucokinase GS, glycogen synthase HFD, high-fat-diet HSL, hormone-sensitive lipase PEPCK, phosphoenolpyruvate carboxykinase PGC1α, proliferator-activated receptor gamma coactivator 1-α PK, pyruvate kinase PP1, Protein phosphatase 1 PTG, protein targeting to glycogen SCD1, stearoyl-CoA desaturase-1 STZ, streptozotocin TAG, triacylglyceride
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Biochemistry