Systems-level analysis of insulin action in mouse strains provides insight into tissue- and pathway-specific interactions that drive insulin resistance.
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Authors
Nelson, Marin E
Madsen, Søren
Cooke, Kristen C
Fritzen, Andreas M
Thorius, Ida H
Masson, Stewart WC
Carroll, Luke
Weiss, Fiona C
Seldin, Marcus M
Potter, Meg
Hocking, Samantha L
Fazakerley, Daniel J
Brandon, Amanda E
Thillainadesan, Senthil
Senior, Alistair M
Cooney, Gregory J
Stöckli, Jacqueline
James, David E
Publication Date
2022-02-01Journal Title
Cell Metab
ISSN
1550-4131
Publisher
Elsevier BV
Volume
34
Issue
2
Pages
227-239.e6
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Nelson, M. E., Madsen, S., Cooke, K. C., Fritzen, A. M., Thorius, I. H., Masson, S. W., Carroll, L., et al. (2022). Systems-level analysis of insulin action in mouse strains provides insight into tissue- and pathway-specific interactions that drive insulin resistance.. Cell Metab, 34 (2), 227-239.e6. https://doi.org/10.1016/j.cmet.2021.12.013
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.
Keywords
GxE, Western diet, adipose, glucose uptake, glycolysis, insulin resistance, metabolism, obesity, proteomics, skeletal muscle
Embargo Lift Date
2023-02-01
Identifiers
External DOI: https://doi.org/10.1016/j.cmet.2021.12.013
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333629
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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