# Effects of the FXR agonist GW4064 on metabolic disorders in db/db mice

## TL;DR

This study shows that the FXR agonist GW4064 improves metabolic issues like obesity and insulin resistance in diabetic mice.

## Contribution

The study demonstrates that FXR activation with GW4064 reduces hepatic steatosis and ER stress in a mouse model of metabolic disorders.

## Key findings

- GW4064 treatment reduced weight gain and improved glucose intolerance and insulin resistance in db/db mice.
- The treatment repressed hepatic steatosis and lowered key lipogenesis and gluconeogenesis gene expressions.
- FXR agonist GW4064 decreased endoplasmic reticulum stress markers in the liver.

## Abstract

Farnesoid X receptor (FXR) is known to play important roles in glucose and lipid metabolism. We aimed to evaluate effects of FXR agonist on metabolic disorders in db/db mice. Seven week-old db/db mice were injected FXR agonist GW4064 (30 mg/kg/day) or carrier solution (dimethyl sulfoxide) intraperitoneally for 4 weeks. Body weight, food intake, and blood glucose levels were measured weekly. Glucose tolerance test and insulin tolerance test were performed at the end of study. Hepatic genes involed in lipogenesis and gluconeogenesis were analyzed by real time polymerase chain reaction. Endoplasmic reticulum stress markers were analyzed by western blot.

GW4064 treatment significantly attenuated weight gain, and improved glucose intolerance and insulin resistance in db/db mice. In addition, GW4064 treatment significantly repressed hepatic steatosis. GW4064 treatment significantly lowered hepatic gene expression of phosphoenolpyruvate carboxykinase 1, glucose 6-phosphatase, and sterol regulatory element binding protein 1c. GW4064 treatment significantly lowered the protein levels of ATF6, CHOP, Caspase3, and Cleaved Caspase3 in liver. FXR agonist GW4064 showed beneficial effects on weight gain, glucose intolerance, insulin resistance, hepatic steatosis, and hepatic ER stress.

These findings suggest that FXR agonists are promising therapeutic agents for treatment of various metabolic disorders.

The online version contains supplementary material available at 10.1186/s42826-025-00251-9.