Farnesoid X receptor (FXR) agonist ameliorates systemic insulin resistance, dysregulation of lipid metabolism, and alterations of various organs in a type 2 diabetic kidney animal model

Abstract

Background Farnesoid X receptor (FXR) plays a role in homeostasis of bile acid, lipid, and carbohydrate metabolism. However, the systemic effects of FXR in diabetic nephropathy are controversial. We aimed to clarify the systemic effects of FXR on various organs in a type 2 diabetic animal model. Methods We treated db/db mice with the FXR agonist GW4064 for 3 months and evaluated insulin resistance, lipid metabolism, renal functional changes, and structural changes in organs including those of the kidney, liver, pancreas, adipose tissue, aorta, and heart. Results The FXR agonist significantly improved plasma lipid profiles and insulin resistance and showed beneficial systemic effects on several organs. In the kidney, the FXR agonist ameliorated albuminuria, pro-fibrotic and pro-inflammatory changes and improved renal lipid metabolism. These changes were also associated with a decrease in lipid hydroperoxide in the kidney. Similar beneficial effects were shown in other organs, including restoration of pancreatic beta cell hypertrophy, hepatic steatosis and aortic medial hypertrophy, more differentiated phenotypic changes in adipose tissue, and improvement of cardiomyocyte disarray and left ventricular mass index. Conclusions The FXR agonist improves insulin resistance, renal lipid metabolism, and functional and structural changes in the kidney and other organs.