New research explains how experimental herb-derived obesity drug works
Sanford-Burnham Medical Research Institute News Apr 28, 2017
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. ThatÂs because there are not yet any good ways to help obese people lose weightÂthe drugs that are available now work no better than diet and exercise, on average leading to a loss of only five percent of a personÂs 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.
ÂKnowing what celastrol does at the molecular level could help drug developers make safer obesity treatments, explains Zhang. ÂCelastrol is too toxic to use as an obesity drug, and weÂre working on modifying it to make it more tolerable, but it may also help to find other molecules that work the same way.Â
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 celastrolÂs target, a receptor called Nur77. Their research, published recently in the journal 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 cellÂs energy plants – where it facilitates the destruction of those that are old and broken down.
ÂOur findings suggest that Nur77 could be a drug target for future anti–obesity drugs, adds Zhang. ÂOther studies have also indicated that this receptor has an important role in regulating metabolism.
ÂNow we want to figure out how celastrolÂs 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.Â
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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.
ÂKnowing what celastrol does at the molecular level could help drug developers make safer obesity treatments, explains Zhang. ÂCelastrol is too toxic to use as an obesity drug, and weÂre working on modifying it to make it more tolerable, but it may also help to find other molecules that work the same way.Â
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 celastrolÂs target, a receptor called Nur77. Their research, published recently in the journal 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 cellÂs energy plants – where it facilitates the destruction of those that are old and broken down.
ÂOur findings suggest that Nur77 could be a drug target for future anti–obesity drugs, adds Zhang. ÂOther studies have also indicated that this receptor has an important role in regulating metabolism.
ÂNow we want to figure out how celastrolÂs 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.Â
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