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Systems-level analysis of insulin action in mouse strains provides insight into tissue- and pathway-specific interactions that drive insulin resistance.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Nelson, Marin E 
Madsen, Søren 
Cooke, Kristen C 
Fritzen, Andreas M 
Thorius, Ida H 

Abstract

Skeletal muscle and adipose tissue insulin resistance are major drivers of metabolic disease. To uncover pathways involved in insulin resistance, specifically in these tissues, we leveraged the metabolic diversity of different dietary exposures and discrete inbred mouse strains. This revealed that muscle insulin resistance was driven by gene-by-environment interactions and was strongly correlated with hyperinsulinemia and decreased levels of ten key glycolytic enzymes. Remarkably, there was no relationship between muscle and adipose tissue insulin action. Adipocyte size profoundly varied across strains and diets, and this was strongly correlated with adipose tissue insulin resistance. The A/J strain, in particular, exhibited marked adipocyte insulin resistance and hypertrophy despite robust muscle insulin responsiveness, challenging the role of adipocyte hypertrophy per se in systemic insulin resistance. These data demonstrate that muscle and adipose tissue insulin resistance can occur independently and underscore the need for tissue-specific interrogation to understand metabolic disease.

Description

Keywords

GxE, Western diet, adipose, glucose uptake, glycolysis, insulin resistance, metabolism, obesity, proteomics, skeletal muscle, Adipocytes, Adipose Tissue, Animals, Insulin, Insulin Resistance, Mice, Muscle, Skeletal

Journal Title

Cell Metab

Conference Name

Journal ISSN

1550-4131
1932-7420

Volume Title

34

Publisher

Elsevier BV