Abstract
Abstract
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.