Celastrol against obesity
In 2015, experts actively discussed the powerful appetite–suppressing effect of celastrol, a compound of plant origin secreted from the three-winged (Tripterygium wilfordii).
When added to the diet of obese mice, celastrol suppressed the appetite of animals by almost 80%, which provided a 45% reduction in body weight. This effect is based on the ability of the compound to increase the sensitivity of the brain to leptin, a hormone that signals the body about saturation. However, until recently, the underlying mechanisms of celastrol action were not known.
Researchers at the Boston Children's Clinical Clinic, working under the guidance of Dr. Umut Ozcan, managed to shed light on this mystery. They demonstrated that the effect of celastrol is mediated by an increase in the expression of the interleukin-1 receptor (IL1R1), which is a component of the proinflammatory signaling pathway. As it turned out, this receptor, which registers signals from a cytokine known as interleukin-1, is in fact a regulator of the metabolic activity of celastrol.
The interleukin-1 receptor was identified through the use of a step-by-step approach. First, the authors studied the effect of celastrol on gene expression in the hypothalamus, a region of the brain that responds to leptin signals. To do this, they formed three groups of animals: lean mice, mice with obesity that developed as a result of overeating, and mice whose obesity was due to the lack of functional receptors for leptin.
When analyzing RNA in animal hypothalamus cells, the researchers identified a group of genes whose activation or inactivation could most likely influence the effects of celastrol. Eventually, their search narrowed down to genes whose expression was altered in obese mice with leptin receptors. The first on this list was the interleukin-1 receptor gene.
According to Ozkan, inactivation of this receptor completely cancels the effect of celastrol on the brain's sensitivity to leptin and appetite. Mice lacking an interleukin-1 receptor were also deprived of other metabolic effects of celastrol, including eliminating tissue sensitivity to insulin and suppressing the development of type 2 diabetes mellitus.
From a scientific point of view, the results obtained are somewhat unexpected, but they do not contradict the results of earlier studies by the authors. According to data published earlier, the relationship between inflammation and obesity is much more complex than previously thought. Traditionally, it was believed that inflammatory stimuli – cytokines or activation of pro–inflammatory signaling pathways - contribute to triggering the development of obesity and type 2 diabetes mellitus. However, the authors demonstrated that the signals of inflammatory mechanisms actually have a beneficial effect and are necessary to maintain glucose homeostasis. In fact, leptin itself is a pro-inflammatory cytokine.
According to Ozkan, most likely, in the field of studying the mechanisms of obesity and diabetes mellitus, inflammatory signaling cascades were mistakenly recognized as a "scapegoat". At the same time, the results obtained by his group indicate that the development of these diseases, on the contrary, is facilitated by violations of the flow of inflammatory signaling cascades. In other words, the problem is that the body acquires resistance to cytokine signals, and not the cytokine activity itself is the problem.
The authors believe that, in any case, the effect on signaling mechanisms through the interleukin-1 receptor will influence metabolism and help in the fight against excess weight. Celastrol has already demonstrated promising results as a weight loss remedy in phase 1 of the clinical trial, however, even if the later stages of the study fail, there may well be other promising areas of work.
In the near future, the authors plan to search for methods for activating the interleukin-1 receptor. This may lead to the development of new drugs for the treatment of obesity and associated diseases based on small molecules. They believe that the data obtained marked the beginning of a new chapter in the history of studying the mechanisms of regulation of hunger.
Article by Xudong Feng et al. IL1R1 is required for celastrol's leptin-sensitivity and antiobesity effects published in the journal Nature Medicine.
Evgenia Ryabtseva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Boston Children's Hospital: How celastrol sensitizes brains to leptin, curbing hunger and obesity.