Celastrol's anti-obesity effects were reported in 2015. Derived from the roots of the thunder god vine, the drug decreased the food intake in obese mice by around 80 percent, producing up to a 45 percent weight loss. It increases the //brain's sensitivity to leptin which signals stomach fullness, but until now, how it acts is unknown. In Nature Medicine, a study led by Umut Ozcan, MD, at Boston Children's Hospital finally solves the mystery.
‘Celastrol controls hunger by changing gene expression in the hypothalamus in which leptin does its signaling.’
Read More..
Ozcan's team initially identified celastrol's effects several years ago, through a screen of more than 1,000 compounds. Ozcan later founded ERX Pharmaceuticals to take celastrol and other leptin sensitizers into clinical development; the company is now testing celastrol in Phase 1 clinical trials.Read More..
The new study shows that celastrol works through a pro-inflammatory signaling pathway, by increasing amounts of a receptor called IL1R1. 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.
Inflammation is good?
Advertisement
"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."
Advertisement
Finding IL1R1
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-Eurekalert