Deletion of the mitochondrial peptidase miPEP in adipose tissue protects against obesity and insulin resistance by increasing adaptive thermogenesis

Mitochondria are pivotal for cellular metabolism, serving as sources and targets of nutrient intermediates from converging metabolic pathways. Here, we demonstrate that insulin resistance leads to a marked alteration in the mitochondrial proteome of adipocytes. Analysis across multiple insulin resistance models revealed a consistent decrease in the level of the mitochondrial processing peptidase miPEP, suggesting a potential role for miPEP in the aetiology of insulin resistance. Adipocyte specific miPEP knockout mice demonstrated a strong phenotype marked by a browning-independent increment in energy expenditure, enhanced insulin sensitivity, and reduced adiposity, despite normal food intake and physical activity. These phenotypes vanished when mice were housed at thermoneutrality suggesting that miPEP deletion triggers a compensatory enhancement in thermogenesis protecting against metabolic dysfunction. Tissue specific analysis of miPEP deficient mice revealed a selective increment in muscle metabolism evidenced by increased basal and insulin induced glucose uptake and upregulation of the protein Fbp2, involved in energy wasting via futile cycling. These findings suggest that miPEP deletion initiates a compensatory increase in thermogenesis, acting as a protective mechanism against diet-induced insulin resistance.