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.