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System level analysis of insulin action revels insight into whole body metabolism and insulin action in muscle and adipose tissue

ABSTRACT: 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 resistance. Adipocyte size profoundly varied across strains and diets, and this was strongly correlated with adipose tissue insulin action. 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Soleus

SUBMITTER: Soren Madsen

LAB HEAD: David E. James

PROVIDER: PXD029680 | Pride | 2022-02-24

REPOSITORIES: Pride

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