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

Abstract

Celastrol, a pentacyclic triterpene is the most potent anti-obesity agent that has been reported to date 1. The mechanism of celastrol's leptin sensitizing and anti-obesity effects has not yet been elucidated. In this study, we identified interleukin 1 receptor 1 (IL1R1) as a mediator of celastrol action by using temporally-resolved analysis of the hypothalamic transcriptome in celastrol-treated DIO, lean and db/db mice. We demonstrate that IL1R1-deficient mice are completely resistant to celastrol's leptin sensitization, anti-obesity, anti-diabetic and anti-NASH effects. Thus, we conclude that IL1R1 is a gate-keeper for celastrol's metabolic actions. Increased ER stress in the hypothalamus plays a central role in the development of leptin resistance, and thus obesity 2-5. Given these findings, we undertook in silico screens utilizing systems biology approaches to identify new chemical chaperones that would serve as stronger leptin sensitizers. These efforts yielded celastrol, a pentacyclic triterpene as a potentially efficacious chemical chaperone and leptin sensitizer 1. Celastrol reduces the body weight of diet-induced obese (DIO) mice by 45-50% and further ameliorates insulin resistance/type-2 diabetes, nonalcoholic steatohepatitis (NASH), hypercholesterolemia, and liver damage in DIO mice 1. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Effectively suppressed angiogenesis-mediated retinoblastoma growth using celastrol nanomicelles

“…Intratumoral hypoxia upregulates the expression of VEGF, which can induce the angiogenesis in tumor . Sato A, et al also found that CoCl 2 -induced hypoxia treatment results in increased the secretion of VEGF in tumor cells (Feng et al, 2019). Once angiogenesis has been activated, tumors exhibit various forms of neovascularization which play a key role in promoting tumor growth, metastasis and invasion.…”

“…HUVECs migration assay was performed as described previously (Feng et al, 2019). Briefly, EA.hy 926 cells were allowed to grow to 90% confluence in gelatin-coated 6-well plates and then incubated with DMEM containing 0.5% FBS for 6 h to inactivate cell proliferation.…”

“…Whether celastrol could modulate retinoblastoma angiogenesis has not been validated yet. Celastrol, a pentacyclic triterpene extracted from Thunder of God Vine, is a potent anti-inflammatory, antiangiogenesis, anticancer and antiobesity agent (Feng et al, 2019). Nevertheless, the further clinical application of celastrol is restricted by its poor water solubility.…”

The Gut Microbiota and Its Metabolites, Novel Targets for Treating and Preventing Non‐Alcoholic Fatty Liver Disease

“…Mice with advanced NASH ↓ ALT levels ↓ Hepatic steatosis ↓ Total hepatic cholesterol [ 100] QHD and GC Rats and mice fed with HFD ↓ Hepatic lipid synthesis ↓ Serum LPS level ↑ Gut barrier function [ 101] DCHD NASH rats fed a high-fat, high-fructose diet ↓ ALT and AST levels ↓ Liver coefficient ↓ Plasma endotoxin [ 102] Baicalin Mice fed with HFD ↓ Weight gain ↓ Hepatic steatosis ↓ Liver fat accumulation ↓ Hepatic TAG and cholesterol [ 103] Celastrol DIO and db/db mice ↓ Hepatic steatosis ↑ Insulin sensitivity ↓ ALT and AST levels [ 108] Ganoderma lucidum and its water extract HFD-fed mice ↓ Fat accumulation ↓ Liver inflammation ↓ Endotoxemia and IR [ 106] Micronutrient antioxidants -cryptoxanthin CL diet-fed mice ↓ Fat accumulation ↓ TBARS level ↓ Hepatic steatosis ↓ Liver inflammation ↓ IR and lipid peroxidation [ 109,110] Astaxanthin CL diet-fed mice ↓ Hepatic steatosis ↑ M2-dominat macrophages ↓ IR and liver inflammation ↓ Liver fibrosis [ 111] Liver samples from NAFLD patients ↓ Hepatic steatosis ↓ Total NAS score Lycopene HFD/CL diet-fed mice ↓ Lipid accumulation in liver ↓ Liver inflammation and IR ↑ M2-macrophage polarization [ 113,114] Vitamin D WD/VDD +/+ diet-fed rats ↑ Hepatic steatosis ↑ TLR4 activity ↑ NAS score [ 116] Vitamin E NASH patients ↓ ALT level ↓ NAS and fibrosis score [ 117] Polyphenols HepG2 cells ↓ ROS, TAG, and ALT ↓ Lipid peroxidation ↑ CAT, GPx, and SOD activities [ 118,165] MCD-fed NASH mice ↓ Hepatic steatosis ↓ ALT and AST level ↓ TBARS level [ 119] Probiotics…”

CNS-targeting pharmacological interventions for the metabolic syndrome

“…Screenings for novel leptin-sensitizing molecules using the bioinformatical Connectivity Map (CMAP) tool led to the identification of the plant constituents celastrol and withaferin A, which increase leptin sensitivity and reduce body weight of obese mice (93,94). The leptin-sensitizing properties of celastrol were later confirmed (95) and attributed to the hypothalamic inhibition of the protein tyrosine phosphatases PTP1B and TCPTP (96) and to an upregulation of the hypothalamic interleukin-1 receptor 1 (IL1R1) (97).…”