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.
Research shows that primary health care providers can promote significant, lasting reductions in drinking levels and alcohol-related problems by asking patients about alcohol use and briefly advising them to reduce risky drinking. In a new study, researchers supported by NIAAA showed that doctors and nurses in an emergency department can also do effective brief interventions for patients who report risky alcohol use. Researchers asked patients who came to the emergency department of a large university hospital about their alcohol use. The nearly 900 adult patients included in the study were found to exceed NIAAA guidelines for low-risk drinking: no more than four drinks in a day and no more than 14 drinks per week for men, and three or fewer drinks per day and no more than seven drinks per week for women. Individuals who received a seven-minute counseling session from a trained emergency practitioner subsequently had significantly lower rates of alcohol consumption and driving after drinking than those who did not, an effect that persisted even a year after the counseling session.
Neuropeptide Y (NPY) is a naturally-occurring brain molecule that helps regulate emotional behavior, stress responses, and other functions. Much research evidence suggests that NPY also plays an important role in regulating alcohol consumption. Scientists led by NIAAA Clinical Director Markus Heilig, M.D., Ph.D., recently investigated the effect of NPY on stress-induced relapse to alcohol use. Relapse prevention is an important aspect of alcoholism treatment, and researchers who study this phenomenon often rely on animal models of relapse-like behavior. Such models usually involve training laboratory rats to obtain alcohol by pressing a lever. Later, the lever-pressing behavior is "extinguished," or unlearned, by removing the alcohol reward. Researchers then simulate alcohol relapse by exposing the animals to stress, which causes them to again seek alcohol by lever-pressing. Stress in rats is reliably induced by injections of yohimbine, a drug that causes anxiety and panic. Using this approach, Dr. Heilig and colleagues from the NIAAA Laboratory of Clinical and Translational Studies found that by injecting rats with NPY, they could suppress the relapse-like alcohol-seeking behavior brought on by yohimbine. The findings, they note, support further study of NPY as a potential treatment for alcoholism.
Neurokinin-1 receptors (NK1R) are highly expressed in brain areas involved in stress responses and drug reward. In recent years, mounting research evidence has suggested that they may help regulate important aspects of alcohol use. In a new study, researchers at the NIAAA report that a compound that blocks NK1R suppresses alcohol drinking in mice. NIAAA Clinical Director Markus Heilig, M.D., Ph.D., and colleagues from the NIAAA Laboratory of Clinical and Translational Studies also showed that mice that lack the gene for NK1R have a lower preference for alcohol than do normal mice, and score lower on measures of alcohol reward, a key aspect of its addictive effects. Taken together, the data from the new study supports further investigation of NK1R blockade as a potential treatment for alcoholism.
Drinking may harm adolescents' ability to concentrate and to understand spatial relationships. A recent study led by Susan Tapert at the University of California, San Diego compared the standardized test scores of 76 12 to 14 year old kids with their scores after about three years. At the three-year follow-up, 36 of the kids had begun drinking at moderate to heavy levels and 40 continued not using alcohol or other drugs. The study defined moderate to heavy drinking as drinking at least monthly and having three or more drinks at a time, or drinking less frequently, but having four or more drinks at a time. The kids in this study were consuming an average of about eight drinks per month by the time they reached the follow-up.
During the study's three-year time period, the team discovered once teens began to drink, they performed more poorly on cognitive tests than before they began drinking. Interestingly, the kinds of skills affected varied between girls and boys.
The researchers found that girls' scores on tasks requiring them to visualize and reproduce a complicated line drawing decreased after they began drinking. The researchers also found that boys' scores on tests requiring sustained attention decreased after they began drinking.
Tapert's study suggests that these behavioral effects may point toward alcohol's underlying effect on brain structure. Brain scans demonstrate that adolescent drinking can reduce the health of white matter in the brain. White matter is where brain cells communicate with each other, so damage to this area can result in slower, less efficient thinking. Reduced white matter integrity may cause girls to have difficulty understanding spatial relationships. This damage may be long-lasting since the adolescent brain is still undergoing significant developmental changes, making it especially vulnerable to alcohol's toxic effects.
Also see: Altered white matter integrity in adolescent binge drinkers, McQueeny T, Schweinsburg BC, Schweinsburg AD, Jacobus J, Bava S, Frank LR, & Tapert SF, Alcoholism: Clinical and Experimental Research, 2009, 33, 1278-1285.