Anti-obesity Drug May Prevent And Treat Obesity-related Liver Disease

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), published by John Wiley & Sons, Inc.

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."

In an accompanying editorial in the same issue, Brent A. Neuschwander-Tetri, of Saint Louis University Liver Center in Saint Louis, MO, notes that while the commonly held belief is that weight loss is achieved by simply burning more calories than are consumed, the reality may not be so simple. Increasing attention is being focused on the cannabinoid signaling system as a major regulator of food energy efficiency and studies have shown that blocking the receptors in this system modifies how ingested calories are processed and has beneficial metabolic effects beyond those attributable to weight loss alone.

He notes, however, that rimonabant trials are weakened by high dropout rates due to side effects such as nausea, dizziness, diarrhea and depression. "Whether pharmacological manipulation of the cannabinoid system with receptor antagonists such as rimonabant will be found to have unacceptable side effects or if such interventions simply adjust the energy efficiency in people with overactive cannabinoid signaling to a healthier level will be decided in time," the author states. "Nonetheless, the emerging understanding of how endogenous cannabinoid signaling regulates food energy efficiency may hammer a very solid nail in the coffin of the dogma that caloric deficit can only be achieved by increased exercise and dietary restriction."

Articles: "Rimonabant Reduces Obesity-Associated Hepatic Steatosis and Features of Metabolic Syndrome in Obese Zucker fa/fa Rats," Magali Gary-Bobo, Ghizlane Elachouri, Jean François Gallas, Philip Janiak, Pietro Marini, Christine Ravinet-Trillou, Michèle Chabbert, Noël Cruccioli, Christian Peersdorff, Claude Roque, Michèle Arnone, Tiziano Croci, Philippe Soubrie, Florence Oury-Donat, Jeane Pierre Maffrand, Bernard Scatton, Frederic Lacheretz, Gérard Le Fur, Jean Marc Herbert, Mohammed Bensaid, Hepatology; July 2007; (DOI: 10.1002/hep.21641).

"Food Energy Efficiency, Cannabinoids, and a Slow Death of the Weight Loss Dogma," Brent A. Neuschwander-Tetri, Hepatology; July 2007; (DOI: 10.1002/hep.21821).