NIAAA researchers advance potential obesity treatment
New research by NIAAA scientists shows that an experimental drug that targets molecular sites in the liver and other tissues without acting on identical sites in the brain, holds promise as an effective treatment for obesity and its complications.
In the July 26, 2012 issue of the journal Cell Metabolism, researchers led by NIAAA Scientific Director George Kunos, M.D., Ph.D., and lead author Joseph Tam, D.M.D., Ph.D., of the NIAAA Laboratory of Physiologic Studies, reported that obese mice that were given the new drug, called JD5037, for about a month lost more than one-fourth of their body weight, and had a reduced appetite for the high-fat diet that had made them obese.
"This is a very promising finding,” says NIAAA acting director Kenneth R. Warren, Ph.D. “Obesity is one of our most pressing public health problems, for which new therapies are urgently needed.”
The current findings are part of ongoing studies by Dr. Kunos and his colleagues on the endocannabinoid system, which regulates appetite and the metabolism of lipids, and is therefore implicated in obesity, diabetes, alcoholism and cardiovascular disease.
While drugs that block brain receptors for endocannabinoids have been found to effectively treat obesity, they also cause serious psychiatric side effects, including anxiety and depression. To try to overcome those side effects, Dr. Kunos and his colleagues tested JD5037, which blocks endocannabinoid receptors in the liver, fatty tissue, kidney, skeletal muscle, and other parts of the body – but not those in the brain.
In addition to weight loss, obese mice that were given JD5037 experienced improved metabolic health, such as reduced insulin resistance, compared with obese mice not given the drug. And as hoped, the drug produced no changes in mouse behavior that would predict psychiatric side effects in people.
Dr. Kunos says the new drug appears to make obese mice more sensitive to leptin, an endogenous hormone that suppresses appetite. He explained that, in obesity, the body becomes less responsive to leptin’s appetite-suppressing effect.
"By sensitizing the body to naturally occurring leptin, the new drug could not only promote weight loss, but also help maintain it," he said.
Next research steps for JD5037 include studies to determine whether it’s safe for humans. Such studies are underway, said Dr. Kunos.