Anti-obesity drug may prevent and treat obesity-related liver disease

A new study on the effect of the anti-obesity drug rimonabant on liver function in obese rats found that it reduced markers of liver damage, decreased levels of pro-inflammatory proteins, and improved lipid profiles.

The results of this study appear in the July 2007 issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD).

Obesity is an inflammatory, chronic and progressive disease that is associated with dramatic changes in the tissue and blood levels of pro-inflammatory and anti-inflammatory proteins and hormones.

It is the main cause of several metabolic syndrome features and their complications, including hepatic steatosis (an accumulation of fat in the liver). There are currently no drugs that have both anti-obesity effects and reverse and prevent obesity-related steatosis and metabolic syndrome, a cluster of conditions such as high blood sugar and high triglycerides that can lead to cardiovascular disease.

Led by Mohammed Bensaid, of Sanofi-aventis Recherche (the company that manufactures rimonabant) in Montpellier, France, researchers studied the effect on the liver of rimonabant, which blocks the cannabinoid receptor CB1, and has been shown to reduce food intake, body weight, and fat mass, and to improve insulin sensitivity and lipid levels in obese rodents and humans. Male obese rats were given rimonabant orally daily for 8 weeks and had their food intake monitored; control animals received the same amount of food as those receiving rimonabant.

The results showed that treatment with rimonabant reduced liver enlargement, completely abolished hepatic steatosis, and decreased blood levels of enzyme markers that indicate liver damage. It also strongly reduced levels of hepatic TNFa, a pro-inflammatory protein that is thought to induce insulin resistance in the liver and be involved in the progression of steatosis to hepatic fibrosis and cirrhosis. “These data reveal that rimonabant possesses a hepato-protective activity and suggest a new therapeutic role of this CB1 receptor antagonist in hepatic diseases,” the authors state. In addition, the results demonstrated that rimonabant improved abnormal lipid levels, which can lead to cardiovascular disease. It reduced levels of cholesterol, free fatty acids and triglycerides, and increased the HDL/LDL ratio. The researchers suggest that this improvement in the lipid profile may be due to the role of rimonabant in restoring the structure and metabolic function of muscle, fat tissue and the liver, all of which are involved in lipid and glucose metabolism. Treatment with rimonabant also normalized levels of adiponectin, a hormone that plays a key role in metabolic disorders.

It is noteworthy that these results were not (or were only slightly observed) in the control animals eating the same diet but not given rimonabant, which demonstrates the beneficial effects of the drug compared to diet alone. “Our hypothesis is that the multi-protective effects of rimonabant may be mediated for a large part by both the reduction in pro-inflammatory cytokines such as TNFa and the increase in anti-inflammatory and protective cytokines or hormones such as adiponectin,” the authors conclude. “This suggests a potential clinical application for this CB1 receptor antagonist in the treatment of liver diseases associated with obesity and the metabolic syndrome.”