When a recent study identified a chemical found in an herb used in traditional Chinese medicine as a potential treatment for obesity, it made headlines. That’s because there are not yet any good ways to help obese people lose weight—the drugs that are available now work no better than diet and exercise, on average leading to a loss of only five percent of a person’s weight.
However, that study was only a first step—the molecular basis for the effects of the compound, called celastrol, was unknown. New research from the lab of Xiao-Kun Zhang, PhD, adjunct professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), identifies the receptor on which celastrol acts and the cellular processes it alters.
“Knowing what celastrol does at the molecular level could help drug developers make safer obesity treatments,” explains Zhang. “Celastrol is too toxic to use as an obesity drug, and we’re working on modifying it to make it more tolerable, but it may also help to find other molecules that work the same way.”
More than one-third of the U.S. adult population, or 74 million people, are obese, putting them at greater risk for type 2 diabetes, heart disease, fatty liver disease, arthritis of the knees, and certain cancers. Finding treatments that help people lose a significant amount of weight could greatly reduce the incidence of these diseases.
Zhang and his lab have identified celastrol’s target, a receptor called Nur77. Their research, published recently in Molecular Cell, shows that celastrol prevents weight gain in mice fed a high-fat diet by altering the function of Nur77. This receptor is normally located in the nucleus, where it controls the activity of specific genes. When celastrol binds Nur77, it moves to the mitochondria—the cell’s energy plants—where it facilitates the destruction of those that are old and broken down.
“Our findings suggest that Nur77 could be a drug target for future anti-obesity drugs,” adds Zhang. “Other studies have also indicated that this receptor has an important role in regulating metabolism.
“Now we want to figure out how celastrol’s effects on mitochondria relate to metabolism. Celastrol seems to make cells more sensitive to leptin, a hormone that inhibits hunger, so we plan to look for connections between Nur77 and leptin signaling in the appetite center of the brain.”