Is IL1R1 required for celastrol’s leptin-sensitization and antiobesity effects?

Yuan Yao,Long Ma*

1State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology(Ministry of Education), Tianjin Key Laboratory of Industry Microbiology, School of Biotechnology, Tianjin University of Science&Technology,Tianjin,China.

The article by Xudong Fenget al.[1], published on 4 March 2019 in the journal ofNature Medicine,showed the relationship between natural product celastrol and obesity.The researchers demonstrated celastrol was able to sensitize leptin and displayed antiobesity effects through IL1R1 (Interleukin-1 receptor 1).It was proved that IL1R1 was a gatekeeper for celastrol’s metabolic actions.

Overweight and obesity are prevalent across the world, which create severe public health concern.According to the World Health Organization, more than 1.9 billion adults (≥18 years) were overweight in 2016.Of these more than 650 million adults were obese with 11% of men and 15% of women.It was estimated that 41 million children (≤5 years) were overweight or obese.Overweight and obesity can be observed at any age and they are more evident for the younger.In 2030, the number of obese people will account for 51% of the whole population [2-3].Consequently, overweight and obesity increase susceptibility to T2DM (Type 2 diabetes mellitus),hypertension, coronary heart disease, stroke and several types of cancers, all of which reduce life quality and lifespan[4,10].

In 1994 and 1995, Friedman and his co-workers published two groundbreaking papers inNatureandSciencerespectively, which opened a new chapter for the treatment development against obesity [5-6].They found that leptin,a hormone secreted by adipose tissue,activated neurons in the hypothalamus and sent a signal of ‘‘I’m full’’ to the brain in order to suppress appetite.However, initial hopes for leveraging leptin’s anorectic effect for treating obesity was less practicable,as it became clear that despite the presence of very high levels of circulating leptin in obese humans, the hormone was ineffective in food intake suppression, owing to leptin resistance [5-7] and perhaps the generalized cytokine resistance [8-9].This is analogous to insulin resistance for diabetic patients.Leptin resistance in fact is common for obesity.

In the year 2015, a team led by Umut Ozcan of Harvard Medical School published a valuable study inCell[10].Ozcan’s team screened more than 1000 compounds that alleviated ER (Endoplasmic reticulum) stress in the hypothalamus, and finally found a drug candidate that could alleviate leptin resistance, namely celastrol [10].Celastrol is an active ingredient of the traditional Chinese medicinal herb,Tripterygium wilfordiiHook F, also known as the Thunder God Vine, which belongs to theCelastraceaefamily.Tripterygium wilfordiiHook F grows mainly in the south and southwest of the Yangtze River Basin in China.According to the records of Chinese ancient booksShennong Bencao Jing(during the third century,Han Dynasty of China ) andBencao Gangmu Shiyi(1765 A.D., Qing Dynasty of China),Tripterygium wilfordiiHook F is poisonous.

Celastrol is commonly used to treat adjuvant arthritis [11], thrombotic and inflammatory [12],neurodegenerative diseases [13] and cancers [14].Recent studies focus on its antiobestiy effect;markedly,it reduces food intake and body weight of diet-induced obese mice by 79% and 45-50% respectively and further ameliorates insulin resistance and T2DM,nonalcoholic steatohepatitis,hypercholesterolemia,and liver damage [10].As an antiobesity drug candidate,celastrol works almost perfectly in mice.

The mechanistic studies have revealed that celastrol is capable of increasing the sensitivity of leptin, which not only reduces the desire to eat and energy intake,but also accelerates the consumption of fat.In addition,celastrol is solely targeted at adipose tissue and does not affect lean body weight, which is rather different from hunger-induced weight loss [1, 10].These characteristics render celastrol as a promising antiobesity drug candidate.

However, researchers initially found leptin resistance, or leptin insensitivity was a prediposing factor of obesity, while the mechanism remained unclear [6, 15].Later it was discovered that ER stress was closely linked to leptin resistance.Although through long-standing research efforts, some agents such as 4-phenyl butyrate and tauroursodeoxycholic acid were found to decrease ER stress to increase leptin sensitivity, their effects were weak [16-17].Before the emergence of celastrol, effective drugs to reduce ER stress to alleviate leptin resistance have not yet been discovered [10].More, the antiobesity mechanisms of celastrol and how it can reduce ER stress remained not full elaborated.

The latest finding from the work done by Xudong Fenget al.[1] was that the antiobseity effect of celastrol was mediated by IL1R1.IL1R1 belongs to the cytokine receptor superfamily and it activates inflammatory signaling pathways [18-19].Celastrol’s leptin-sensitizing effect required both high levels of circulating leptin and intact leptin receptor signaling.Leptin only worked when IL1R1 functions properly[1].After induction of obesity,Il1r1+/+andIl1r1–/–mice were treated with either vehicle or celastrol.Celastrol significantly decreased the body weight ofIl1r1+/+mice, but failed to decrease the body weights ofIl1r1–/–mice.The reduction in food intake observed in celastrol-treatedIl1r1+/+mice was abolished inIl1r1–/–mice.Celastrol did not alter lean body mass in either group [1].In the absence of IL1R1, the effects of celastrol on mice such as antiobesity,anti-diabetes and fatty liver were completely lost, and the food intake of mice was no longer under control [1].It was also confirmed that celastrol reduced food intake in mice,not by inducing disease-related factors and had no negative effects on sociability or normal social preferences [1].No significant toxic effects were observed in mice treated with celastrol over a longer period of time.To some extent, celastrol is safe.Further study showed that ER stress inhibited leptin signaling in the hypothalamus leading to food intake and weight gain in mice; interestingly, celastrol was able to enhance the effect of leptin by activating the hypothalamic leptin receptor-1 signal transduction and the transcriptional activator 3 signaling pathway to alleviate ER stress[1].

Apart from current research, other mechanisms of celastrol have been reported by other groups.For examples, celastrol is proved to suppress weight and attenuate high fat mediated oxidative in previously published papers.It exerts effect by effectively attenuating high fat emulsion mediated oxidative stress injury and ameliorating blood lipid metabolism[20].In addition, in the year 2017, a team led by Xiao-kun Zhang from Xiamen University, found that celastrol was able to bind Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner, thus saving mice from obesity caused by a high-fat diet[21].

Celastrol increases the brain’s sensitivity to leptin,but no one knew the reasons until the report by the Umut Ozcan’s team was finally published [1].From a scientific point of view, this finding seems somewhat counterintuitive.It is generally believed that the activation of inflammatory signaling pathways contributes to the development of obesity and T2DM[21-22].But Ozcan and his colleagues in fact have shown that inflammatory signaling pathways activated by IL1R1 are beneficial when using celastrol as antiobesity agent.

Previous studies have shown that celastrol could treat obesity in a number of ways.Nevertheless, it should be very cautious to useTripterygium wilfordiiHook F without medical consultation, since it contains a variety of extremely toxic components that are harmful to liver, nervous system and kidney.Whether celastrol will work in humans or not will depend on the results of clinical trials.We will wait and see!