How genes interact with environmental factors is central to the development of cardiometabolic disease, however, most studies in mice examine these factors in isolation, and investigations across multiple organ systems are rare. To address this, we interrogated the susceptibility of 11 genetically divergent mouse strains to diet-induced metabolic defects and performed a deep proteomic analysis of 4 metabolically important tissues. Leveraging comprehensive metabolic phenotyping, including of liver and peripheral tissue insulin sensitivity, this study is uniquely placed to determine the precise contributions of individual organs to systemic metabolism.
Diet-induced hyperglycaemia was most strongly associated with the development of cardiac insulin resistance. Additionally, these data further suggest that cardiac insulin resistance may provide a mechanistic link between Type 2 Diabetes and cardiovascular disease, as cardiac insulin resistance was accompanied by fibrosis and the accumulation of toxic ceramide species. To prioritise causal molecular candidates, we developed a biologically informed machine learning framework and identified mitochondrial ribosomal protein MRPL44 at the nexus of insulin resistance and cardiac remodelling. Strikingly, cardiac MRPL44 explained differences in brown adipose oxidative phosphorylation independently of MRPL44 expression in brown adipose itself, suggesting that dysregulated crosstalk between these tissues may play a central role in modulating systemic metabolic health.