Cedars-Sinai scientists noted that the effects of an anti-obesity drug, rimonabant, a CB1 antagonist, were promising in peripheral tissue such as fat and the liver. Despite the drug being removed from the market for side effects such as depression and anxiety in some users, the positive effects warrant more investigation. Rimonabant acts on the endocannabinoid system targeting CB1 receptors located in the brain and throughout the body. Scientists at the Cedars-Sinai Diabetes and Obesity Research Institute (DORI) are examining the prospect of a limited-penetrating CB1 receptor antagonist in the brain that maintains the positive effects on fat and liver tissues to improve diabetes and obesity.
Previous animal studies at DORI showed that rimonabant diminished adipocytes cell size and improved adipocyte distributions. Four sizes of fat cells were identified by fat feeding: small, normal, large and very large. Rimonabant shrank large and very large cells to normal size. As adipocyte size plays a key role in the development of insulin resistance, understanding what happens in each size category may assist in developing a compound that targets adipocytes.
Morvarid Kabir, PhD, is a molecular biologist and assistant professor at DORI who studies hepatoprotective effects of CB1 antagonists. She demonstrated that an increased delivery of adiponectin — a protein produced and secreted exclusively by fat cells that regulates the metabolism of lipids and glucose — from visceral fat to the liver acts on its own receptors, adiponectin 1 and 2, thereby improving fat oxidation and reducing inflammatory cytokine expression in the liver.
Recent studies have demonstrated that CB1 receptor antagonists increased expression of the genes involved in browning of fat. Increased browning of fat, particularly in the visceral fat depot, appears to be an important mechanism by which antagonism of the cannabinoid system regulates body fat and metabolism. Additional research to elucidate the mechanism by which the endocannabinoid system regulates body fat and metabolism is underway. DORI scientists are pursuing these studies in search of therapies to assist in treating obesity and Type 2 diabetes.
Current areas of study regarding CB1 receptor antagonists in the liver and adipose tissue include:
- Hepatoprotective effects of CB1 antagonist:
- Feed animal model a high-fat diet for six weeks to induce mild obesity.
- Maintain high-fat diet for additional 16 weeks with some subjects receiving a placebo and others receiving rimonabant.
- Determine how rimonabant treatment effects expression of several genes in different pathways in the liver, such as lipid oxidation, lipogenesis, gluconeogenesis and inflammation.
- Increased browning of white adipose tissue contributes to the beneficial metabolic effects of inhibition of the cannabinoid regulating system in vivo.
- Feed animal model a high-fat diet to increase both visceral and subcutaneous fat for six weeks.
- For 16 weeks, feed some participants a high-fat diet plus placebo, while others receive a high-fat diet with rimonabant.
- Obtain biopsies from visceral and subcutaneous fat tissues before high-fat feeding and after 16 weeks of placebo or rimonabant treatment.
- Examine longitudinal effects of high-fat diet and rimonabant on genes involved in the process of fat browning.