How celastrol sensitizes brains to leptin, curbing hunger and obesity

Celastrol's potent anti-obesity effects were widely reported in 2015. Derived from the roots of the thunder god vine, the drug curbed food intake in obese mice by nearly 80 percent, producing up to a 45 percent weight loss. Celastrol increases the brain's sensitivity to leptin, the hormone that signals we've had enough to eat, but until now, no one knew how. In today's Nature Medicine, a study led by Umut Ozcan, MD, at Boston Children's Hospital finally solves the mystery.

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.

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?

Scientifically, the finding seems 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.

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."

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.

Most Popular Now

Walnuts may help lower blood pressure for those at…

When combined with a diet low in saturated fats, eating walnuts may help lower blood pressure in people at risk for cardiovascular disease, according to a new Penn State ...

Bristol-Myers Squibb reports first quarter financi…

Bristol-Myers Squibb Company (NYSE:BMY) today reported results for the first quarter of 2019 which were highlighted by strong demand for Opdivo (nivolumab) and Eliquis (a...

Amgen ignites a social fitness movement to support…

Amgen (NASDAQ:AMGN) launched the Breakaway Challenge initiative, a national social fitness program to motivate individuals to take action in their health and to support t...

Possible link between autism and antidepressants u…

An international team led by Duke-NUS Medical School has found a potential link between autistic-like behaviour in adult mice and exposure to a common antidepressant in t...

AstraZeneca starts artificial intelligence collabo…

AstraZeneca and BenevolentAI today began a long-term collaboration to use artificial intelligence (AI) and machine learning for the discovery and development of new treat...

Researchers define Alzheimer's-like brain disorder

A brain disorder that mimics symptoms of Alzheimer's disease has been defined with recommended diagnostic criteria and guidelines for advancing future research on the con...

Comprehensive tumor profiling promises new therape…

The WINTHER trial, NCT01856296, led by investigators from Vall d'Hebron Institute of Oncology - VHIO (Spain), Chaim Sheba Medical Center (Israel) (Raanan Berger), Gustave...

Amgen and Syapse enter precision medicine collabor…

Amgen (NASDAQ:AMGN), a world leader in biotechnology, and Syapse, a company powering precision medicine insights through its global provider network, announced a precisio...

Drugs to prevent stroke and dementia show promise …

Treatments that prevent recurrence of types of stroke and dementia caused by damage to small blood vessels in the brain have moved a step closer, following a small study...

Novartis presents first-of-its-kind algorithm-base…

Novartis today announced results from a validation study of the innovative, algorithm-based digital solution MS Progression Discussion Tool, or MSProDiscussTM. The tool a...

Trastuzumab deruxtecan demonstrated clinically-mea…

AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) today announced positive top-line results for the pivotal Phase II DESTINY-Breast01 trial of trastuzumab ...

Genetic therapy heals damage caused by heart attac…

Researchers from King's College London have found that therapy that can induce heart cells to regenerate after a heart attack. Myocardial infarction, more commonly known ...