Steap4 controls adipocyte thermogenesis and energy expenditure by modulating mitochondrial function

Steap4, a highly expressed protein in adipose tissue, has been implicated in metabolic homeostasis. In this study, we generated adipocyte-specific Steap4-deficient mice and observed that Steap4 deficiency led to increased fat mass and severe insulin resistance in a high-fat diet model. Mass spectrometry analysis revealed two classes of Steap4 interactomes: mitochondrial proteins and proteins involved in spliceosome. RNA-seq analysis of white adipose tissue demonstrated that Steap4 deficiency altered RNA splicing patterns with enriched functions in mitochondria. While interactome and transcriptome data implicate a role of Steap4 in mitochondria, Steap4 deficiency indeed impaired mitochondrial respiratory chain complex activity resulting in mitochondrial dysfunction in white adipose tissue. Consistently, brown adipocyte-specific Steap4-deficient mice also showed impaired mitochondrial function, increased whitening of brown adipose tissue, reduced energy expenditure, and exacerbated insulin resistance under HFD conditions. Overall, our findings elucidate the critical role of Steap4 in regulating adipocyte thermogenesis and energy expenditure by modulating mitochondrial function.