Journal
CELL METABOLISM
Volume 34, Issue 2, Pages 227-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2021.12.013
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Funding
- National Health and Medical Research Council (NHMRC) [GNT1086851]
- Danish Diabetes Academy
- Novo Nordisk Foundation [NNF17SA0031406, NNF16OC0023080]
- Benzon Foundation
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Insulin resistance can occur independently in skeletal muscle and adipose tissue, highlighting the importance of tissue-specific investigation in understanding metabolic diseases.
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.
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