CNIH4 in TA MUSCLE about glucose metabolism and endurance ability
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.