Medindia
Advertisement

How Celastrol Sensitizes Brain to Leptin, Curbing Hunger

by Ramya Rachamanti on March 5, 2019 at 4:57 PM
Font : A-A+

How Celastrol Sensitizes Brain to Leptin, Curbing Hunger

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.

Advertisement


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.
Advertisement

"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."



Source: Eurekalert
Advertisement

Advertisement
News A-Z
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
News Category
What's New on Medindia
Gonorrhea
World Alzheimer's Day 2021 - 'Know Dementia, Know Alzheimer's
'Hybrid Immunity' may Help Elude COVID-19 Pandemic
View all

Medindia Newsletters Subscribe to our Free Newsletters!
Terms & Conditions and Privacy Policy.

More News on:
Parkinsons Disease Parkinsons Disease Surgical Treatment Brain Brain Facts Ataxia Hungry? - But you Just Ate! Why does your Stomach Growl with Hunger Language Areas in The Brain Ways to Improve your Intelligence Quotient (IQ) Fullness Factor, Satiety Index and Glycemic Index for Weight Watchers 

Recommended Reading
Obesity
Obesity is a condition where there is excess accumulation of body fat which poses a risk to the ......
Ataxia
Ataxia affects coordination. Gait becomes unstable and the patient loses balance. The cerebellum or ...
Fullness Factor, Satiety Index and Glycemic Index for Weight Watchers
Weight loss is a struggle for many individuals. This can be achieved simply by understanding the ful...
Hungry? - But you Just Ate!
Most of us are tempted by good food, mealtime or not. Once in a way is fine but it is dangerous to g...
Language Areas in The Brain
The mechanism of how human brain processes the language to express and comprehend the verbal, writte...
Parkinsons Disease
Parkinson’s disease is a neurodegenerative disease caused by progressive dopamine brain cells loss. ...
Ways to Improve your Intelligence Quotient (IQ)
Intelligence quotient (IQ) is a psychological measure of human intelligence. Regular physical and me...
Why does your Stomach Growl with Hunger
A rumbling, growly stomach, hiccups and continuous sneezing are some of the body’s signals which we ...

Disclaimer - All information and content on this site are for information and educational purposes only. The information should not be used for either diagnosis or treatment or both for any health related problem or disease. Always seek the advice of a qualified physician for medical diagnosis and treatment. Full Disclaimer

© All Rights Reserved 1997 - 2021

This site uses cookies to deliver our services. By using our site, you acknowledge that you have read and understand our Cookie Policy, Privacy Policy, and our Terms of Use