CNIH4 regulates systemic metabolism and exercise adaptations in male mice primarily through the modulation of β-adrenergic receptor trafficking

Exercise improves glucose and lipid metabolism by remodeling skeletal muscle and adipose tissue, processes that depend on beta-adrenergic receptor signaling. How receptor trafficking and activation are coordinated across tissues remains unclear. Here we show that Cornichon homolog 4 controls beta-adrenergic receptor localization and activity in metabolic tissues. Cornichon homolog 4 expression increases in human and mouse skeletal muscle after resistance training. Loss of Cornichon homolog 4 in all tissues or skeletal muscle impairs beta2-adrenergic receptor trafficking and causes exercise-induced hyperglycemia and defective glucose use. Its loss also worsens diet-induced obesity. In adipose tissue, loss of Cornichon homolog 4 weakens beta3-adrenergic receptor signaling, thermogenesis and exercise-induced lipolysis. Pharmacological activation of beta2- or beta3-adrenergic receptors partially restores glucose or adipose defects. Mechanistically, Cornichon homolog 4 links adrenergic receptor signaling to extracellular matrix gene expression and Smad signaling. These findings identify Cornichon homolog 4 as a coordinator of metabolic adaptation. Liu et al. show in male mice that CNIH4 helps adrenaline receptors reach cell surfaces, supporting skeletal muscle glucose use and uphill exercise performance, while promoting brown fat breakdown and heat production in adipose tissue.