CNIH4 regulates metabolic adaptations to exercise through β-adrenergic receptor-mediated ECM remodeling

Abstract Exercise generates various metabolic benefits by inducing extensive metabolic remodeling in skeletal muscle and adipose tissue, which is primarily mediated by β-adrenergic receptor (β-AR) signaling. However, how β-AR trafficking and activation are coordinated across metabolic tissues remains unclear. Here, we identify Cornichon homolog 4 (CNIH4) as a key regulator of β-AR membrane localization and downstream metabolic responses to exercise. Indeed, Cnih4 expression is upregulated in both human and mouse skeletal muscle following resistance training. Global (Cnih4 KO) and muscle-specific (Cnih4MKO) deletion of Cnih4 in mice impairs β₂-AR trafficking and PI3K–AKT signaling, resulting in exercise-induced hyperglycemia and defective glucose utilization. Additionally, Cnih4 KO accelerated high-fat diet (HFD)-induced obesity and metabolic dysfunction. Adipose-specific Cnih4 knockout mice (Cnih4AKO) phenocopied Cnih4 KO in terms of metabolic dysfunction and inhibited brown adipose tissue (BAT) thermogenesis, due to impaired β3-AR signaling. Furthermore, loss of Cnih4 blocked exercise-induced lipolysis in adipose tissue. Notably, pharmacological activation of β-AR signaling partially rescued these metabolic defects in Cnih4-deficient mice: a β2-AR agonist specifically restored glucose metabolism in Cnih4MKO mice, while a β3-AR agonist ameliorating adipose tissue dysfunction in Cnih4AKO mice. Mechanistically, CNIH4 regulated extracellular matrix (ECM) gene expression through β-ARs-SMAD signaling. These findings demonstrate that CNIH4 acts as crucial modulator of tissue-specific metabolic adaptations to exercise via β-AR signaling, and highlight CNIH4 may be a potential therapeutic target for obesity and related disorders.