Orosomucoid Enhances Insulin Sensitivity via the C–C Chemokine Receptor Type 5/Protein Kinase B Axis

Insulin resistance is a central pathological feature underlying various metabolic disorders, involving complex mechanisms and multi-organ dysfunction. This study investigates the role of the acute-phase protein orosomucoid in systemic glucose homeostasis. This study utilized high-fat diet–induced obese mice to model insulin resistance. The genetic deletion of orosomucoid 1 was applied, and the metabolic effects of exogenous orosomucoid administration were examined. Molecular analysis included assessing protein kinase B phosphorylation. The dependency of observed benefits on specific receptors was tested using pharmacological inhibition of C–C chemokine receptor type 5 and evaluation of the leptin receptor’s role. We demonstrate that genetic deletion of orosomucoid 1 induces insulin resistance, whereas exogenous orosomucoid administration improves glucose tolerance and insulin sensitivity in high-fat diet mice. At the molecular level, orosomucoid augments insulin-induced protein kinase B phosphorylation. Notably, these metabolic benefits are independent of the leptin receptor but are critically dependent on the C–C chemokine receptor type 5, as demonstrated by pharmacological inhibition. Our findings establish orosomucoid as an endogenous insulin sensitizer via the C–C chemokine receptor type 5/protein kinase B pathway, coordinately ameliorating insulin resistance across multiple metabolic organs and highlighting its therapeutic potential as a novel target for metabolic disorders.