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Celastrol increases the number of IL1R1 receptors in the brain

Celastrol increases the number of IL1R1 receptors in the brain

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Celastrol increases the number of il1r1 receptors in the brain, allowing leptin to act. (illustration: ella maru studio)

Here’s what’s known about celastrol, widely hailed in 2015 for its potent anti-obesity effects. It’s derived from the roots of the thunder god vine. It increases the brain’s sensitivity to leptin, the hormone that signals we’ve had enough to eat. It has curbed food intake by nearly 80 percent in obese mice, producing up to a 45 percent weight loss. It’s now in Phase 1 clinical trials conducted by ERX Pharmaceuticals; phase 2 studies are slated to begin this year.

What hasn’t been known is how celastrol makes the brain more sensitive to leptin. A study in today’s Nature Medicine finally provides an answer.

A team led by Umut Ozcan, MD, in the Division of Endocrinology at Boston Children’s Hospital, originally identified celastrol through a screen of more than 1,000 compounds. Ozcan later founded ERX to take celastrol and other leptin sensitizers into clinical development.

Now, Ozcan and colleagues show 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.

This is a new chapter for understanding the regulation of hunger.

“If you knock out IL1R1, the leptin-sensitizing and anti-obesity effects of celastrol are 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 and type 2 diabetes.

Inflammation is good?

Scientifically, the finding seems somewhat surprising. Inflammatory stimuli — cytokines or activation of inflammatory signaling pathways — had been thought to help drive the development of obesity and type 2 diabetes.

But studies published by Ozcan’s team in Nature Medicine (2011) and Cell (2017) suggest that the relationship between inflammation and obesity is more complex than previously appreciated. Those studies showed that inflammatory signaling is actually beneficial and required for keeping glucose homeostasis in control. In fact, leptin itself is a pro-inflammatory cytokine, notes Ozcan.

The thunder god vine, source of celastrol
The thunder god vine, source of celastrol (photo: qwert1234/wikimedia commons)

“I believe that inflammatory signaling cascades have been wrongly regarded as the scapegoat of obesity and diabetes research,” he 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.

Finding IL1R1

Ozcan’s team identified ILR1’s role 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 in each group, Ozcan and colleagues created a list of genes whose up- or down-regulation could plausibly account for celastrol’s effects.

Eventually, their search narrowed to genes altered in the obese mice that retained their leptin receptors. IL1R1 rose to the top of the list.

Listening to leptin

Thus far, celastrol is producing encouraging weight-loss results in the early-stage clinical trials. But should it ultimately fail, the IL1R1 finding raises new potential 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.”

Xudong Feng, PhD, and Dongxian Guan, PhD, of the Division of Endocrinology at Boston Children’s Hospital were co-first authors of the paper. The study was funded by the Department of Medicine at Boston Children’s Hospital, the National Institutes of Health and Fidelity Biosciences Research Initiative. Ozcan is a scientific founder, shareholder and member of the board of directors of ERX Pharmaceuticals.

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