The role of indoleamine 2,3-dioxygenase in stress-induced metabolic disorders

Abstract

Abstract Depression is considered the second leading cause of the global health burden after cancer. Depression doubles the risk of metabolic syndrome in the overall population. Depressed people are more vulnerable to metabolic syndrome because of their poor health-related practices. The regulatory key factors between metabolic diseases and depression are poorly understood in terms of dysregulation of genes affected in depressive disorder. We employed in silico analysis and quantitative framework to understand the molecular mechanism of depression and its related metabolic diseases. According to the previous studies, the key regulator of tryptophan metabolism, IDO-1, plays an important role in the pathophysiology of depression. In the present study, molecular docking and simulation analyses were performed to determine the interaction kinetics of Indoleamine 2,3-dioxygenase (IDO-1) with drugs, including metformin, pioglitazone and alpha- tocopherol, which are widely used in the treatment of diabetes and non-alcoholic steatohepatitis (NASH). Our study aims to outline the effect of IDO1 on hepatic lipid metabolism in vitro and in vivo. We found that stressed mice showed the improved glucose and insulin tolerance compared to the control group. IDO-1 expression robustly increased in the serum of high-fat diet-induced stressed mice. In vitro study confirms that knocked down of IDO-1 aggravated lipid droplets in AML-12 hepatocytes treated with free fatty acids and upregulated the mRNA expression of lipid metabolic genes. Hence, IDO-1 may contribute a significant role in hepatic lipid metabolism. Taken together, our findings suggest that IDO-1 may inhibit the of lipid accumulation in the liver and can serve as a potent drug target for pioglitazone to combat metabolic abnormalities along with stress prevention.