How celastrol sensitizes brains to leptin, curbing hunger and obesity

March 04, 2019

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."
-end-
Xudong Feng, PhD, and Dongxian Guan, PhD, of the Division of Endocrinology and F.M. Kirby Neurobiology Center 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.

Boston Children's Hospital

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.