Although it has long been used in traditional Chinese medicine to treat conditions including rheumatoid arthritis and psoriasis, regulatory bodies have warned against the use of celastrol due to the potential for nasty side effects. But the compound has drawn interest in anti-obesity research circles of late, with studies showing it can prevent and even reverse the condition in mice, and now a new understanding of how the compound works on a cellular level could allow the side effects to be avoided.

In 2018, we looked at study centering on the weight-loss effects of celastrol, a chemical compound found in the roots of the “thunder god vine” and “Regel’s threewingnut” plants. This study in mice showed that the compound can combat obesity by restoring function of a hormone called leptin, which plays a key role in the regulation of appetite by letting us know when we’ve had enough to eat.

Obesity can compromise the performance of this key hormone, causing the leptin receptors in the brain to malfunction and the “fullness” signals to not arrive as they should, leading the person to overeat and continue to gain weight. These earlier experiments showed that celastrol restored leptin sensitivity in overweight mice, which corresponded with an average loss in body weight of around 10 percent in just one week.

Research has also shown, however, that celastrol can cause side effects such as high blood pressure and lethargy in mice, so work continues to pinpoint its specific weight loss mechanisms in the hope that they can be isolated and translated into advanced treatments for obesity. Scientists at the University of Texas Southwestern have uncovered key new details through further experiments in mice.

Mice administered the compound were found to have decreased activity of a protein called PERK, which lives in the same brain region as neurons called POMCs. Previous research has shown POMCs to be associated with reduced appetite, lower blood glucose levels and improved energy burning, and this new study showed they play a central role in how celastrol drives weight loss via the inhibition of the PERK protein. Deleting the PERK protein from the POMC neurons was then found to mimic much of the weight loss effects of celastrol, conferring protection against diet-induced obesity in male mice, but without the adverse side effects.

“The mice were leaner and had the same activity levels; they didn’t appear lethargic, sickly or ill,” says study author Kevin W. Williams. “But this is through observation only. Further study is needed to verify how targeting this pathway may be influencing their cardiovascular systems and other functions.”

Part of these further investigations will focus on the other cell types that might be implicated in celastrol’s effects on metabolism, to build a fuller picture of the complex pathways at play.

“This new understanding of how celastrol works on the cellular level opens more possibilities for targeting pathways that can improve our metabolism without the negative health impact,” says Williams. “We haven’t uncovered all the cell populations that influence weight loss, but each of these findings brings us closer to developing effective, safe therapies for obesity.”

The research was published in the journal JCI Insight. 

Source: University of Texas Southwestern