Celastrol, a natural compound isolated from a traditional Chinese medicine, Thunder God Vine, has been shown to possess potent anti-obesity effects. Derived from the roots of Tripterygium wilfordii, celastrol has been shown to reduce food intake in obese mice by nearly 80 percent, producing up to a 45 percent weight loss. The compound increases the brain’s sensitivity to leptin, the hormone that signals we’ve had enough to eat, but until now, no one knew how it worked. A new paper published in Nature Medicine has finally solved the mystery.
A team of researchers led by Umut Ozcan, MD, of Boston Children’s Hospital, initially identified celastrol’s effects several years ago after screening more than 1,000 compounds. Their new study reveals that celastrol works by increasing amounts of a receptor called IL1R1 through a pro-inflammatory signaling pathway. This receptor, which receives signals from the cytokine interleukin 1, is essentially the gatekeeper for celastrol’s metabolic actions, the study found.
“If you knock out IL1R1, the leptin-sensitizing and anti-obesity effect of celastrol is completely gone,” says Ozcan, the study’s senior investigator. Mice deficient in IL1R1 also lost celastrol’s other metabolic benefits, which include curbing insulin resistance/type 2 diabetes.
Scientifically, the finding is somewhat surprising, but it is in line with Ozcan’s previous discoveries. Papers published in Nature Medicine (2011) and Cell (2017) indicate that the relationship between inflammation and obesity seems to be more complex than previously appreciated. Inflammatory stimuli — cytokines or activation of inflammatory signaling pathways — had been thought to help drive the development of obesity and type 2 diabetes.
But Ozcan and his colleagues showed that inflammatory signaling is actually beneficial and required for keeping glucose homeostasis in control. In fact, leptin itself is a pro-inflammatory cytokine.
“Basically, I believe that inflammatory signaling cascades have been wrongly regarded as the scapegoat of obesity and diabetes research,” Ozcan says. “On the contrary, our work has shown that it is probably the dysfunction of pro-inflammatory signaling pathways that contributes to the development of obesity and type 2 diabetes. The problem is that the body becomes resistant to cytokine signaling, rather than cytokine action being the problem.”
In any event, the researchers believe that it may be possible to make use of cytokine signaling, via ILR1, to alter our metabolism and help us lose weight.
ILR1 was identified through a stepwise approach. The researchers first investigated how celastrol changes gene expression in the hypothalamus, the part of the brain where leptin does its signaling. They created three groups: lean mice, mice made obese by overfeeding and mice that were obese because they lacked functioning leptin receptors.
By analyzing RNA in the hypothalamus from all three groups, Ozcan and colleagues homed in on a group of genes whose up- or down-regulation could plausibly account for celastrol’s effects. Ultimately, their search narrowed to genes altered specifically in the overfed obese mice, which still had leptin receptors. IL1R1 rose to the top of the list.
The IL1R1 finding offers new potential options for obesity treatment. Celastrol is producing encouraging weight-loss results so far in the early-stage trials, but should it ultimately fail, there may now be other avenues to explore.
“We will now investigate what upregulates IL1R1,” says Ozcan. “It could lead to development of new molecules for the treatment of obesity and associated diseases. This is a new chapter for understanding the regulation of hunger.”
Source: Xudong Feng, Dongxian Guan, Thomas Auen, Jae Won Choi, Mario Andrés Salazar Hernández, Jaemin Lee, Hyonho Chun, Farhana Faruk, Esther Kaplun, Zachary Herbert, Kyle D. Copps, Umut Ozcan. IL1R1 is required for celastrol’s leptin-sensitization and antiobesity effects. Nature Medicine, 2019; DOI: 10.1038/s41591-019-0358-x