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Celastrol as a tool for the study of the biological events of metabolic diseases

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  • ReceivedNov 3, 2018
  • AcceptedDec 11, 2018
  • PublishedFeb 25, 2019

Abstract


Funded by

Professor of Chang Jiang Scholars Program

the National Natural Science Foundation of China(81520108030,21472238,81502956,21572064,21525209,21621002,21772225,21761142003)

Chinese Academy of Sciences(Strategic,Priority,Research,Program,XDB20000000,Key,Research,Program,of,Frontier,Sciences,QYZDB-SSW-SLH040)

Shanghai Science and Technology Commission(15JC1400400,17XD1404600)

the National Program for Support of Top-Notch Young Professionals of China

the K. C. Wong Education Foundation

and the State Key Laboratory of Innovative Natural Medicine and Traditional Chinese Medicine Injections(QFSKL2017003,QFSKL2017004)


Acknowledgment

This work was supported by Professor of Chang Jiang Scholars Program, the National Natural Science Foundation of China (81520108030, 21472238, 81502956, 21572064, 21525209, 21621002, 21772225, 21761142003), Chinese Academy of Sciences (Strategic Priority Research Program XDB20000000 and Key Research Program of Frontier Sciences QYZDB-SSW-SLH040), Shanghai Science and Technology Commission (15JC1400400, 17XD1404600), the National Program for Support of Top-Notch Young Professionals of China, the K. C. Wong Education Foundation, and the State Key Laboratory of Innovative Natural Medicine and Traditional Chinese Medicine Injections (QFSKL2017003, QFSKL2017004).


Interest statement

The authors declare that they have no conflict of interest.


Contributions statement

These authors contributed equally to this work.


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  • Figure 1

    The structure of celastrol. The para-quinone methide moiety is highlighted in red (color online).

  • Figure 2

    Celastrol sensitizes leptin through reversing endoplasmic reticulum stress and thus combats obesity. The signal communication between the peripheral organs and the CNS regulates energy homeostasis (intake versus expenditure) that ultimately determines the body weight. The hormone leptin is secreted by adipocytes and controls the communication of satiety signal. It functionalizes through binding to its receptor LepRb expressed on the neurons in the hypothalamus of CNS. Activation of LepRb by leptin leads to phosphorylation of LepRb at Tyr1138, which further results in the recruitment and activation of a regulator of energy balance, namely signal transducer and activator of transcription 3 (STAT3). The LepRb-STAT3 signaling is crucial for energy expenditure. However, ER stress causes leptin resistance and thus inhibits this signaling pathway. Celastrol can reverse reticulum (ER) stress and sensitize leptin in DIO mice, which results in suppression of food intake and loss of body weight (color online).

  • Figure 3

    Celastrol activates HSF1-PGC1α axis in adipose tissue and skeleton muscle and thus protect against obesity. Heat shock transcription factor 1 (HSF1) is a key metabolic regulator responding to metabolic and environmental stress. HSF1 maintains an inactive form in the cytoplasm by forming a complex with a series of heat shock proteins (HSP) including HSP90. Celastrol induces the dissociation of HSF1 from the complex and translocation of HSF1 to the nucleus. In the nucleus, HSF1 upregulates expression of a transcription factor peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α). PGC1α can stimulate mitochondrial biogenesis that ultimately results in enhancement of energy expenditure and thermogenesis in adipose tissue and muscle and browning of white adipose tissue (WAT) (color online).

  • Figure 4

    Celastrol alleviates inflammation through Nur77 mediated mitophagy and thus exerts anti-obesity effect. Chronic inflammation plays an important role in the development of obesity. Nuclear factor κB (NF-κB) is a central regulator of inflammation, and celastrol is known to antagonize the NF-κB pathway. Indeed, celastrol can bind to an orphan nuclear receptor Nur77, which results in translocation of Nur77 to the mitochondria. Nur77 interacts with E3 ubiquitin ligase tumor necrosis factor receptor-associated factor 2 (TRAF2), which induces autophagy of mitochondria (mitophagy). Nur77-dependent mitophagy proves to be the upstream event of the inhibition of NF-κB pathway by celastrol (color online).

  • Figure 5

    Celastrol protects against insulin-resistance via TLR4/NF-κB signaling pathway. The hormone insulin is secreted by β cells of pancreas in response to nutritional uptake. Insulin promotes the absorption of glucose from blood to various organs. Insulin resistance refers to the pathological condition in which cells of the target organs are unable to response normally to insulin; it is a hallmark of type 2 diabetes. An excess of circulating free fatty acids (FFAs) in the liver induce Toll-like receptor 4 (TLR4) dependent inflammation that ultimately leads to insulin resistance. In particular, palmitic acid (PA, the most abundant FFA) binds to myeloid differentiation factor 2 (MD2) that is associated with the extracellular domain of TLR4. This triggers the interaction of myeloid differentiating primary response 88 (MyD88) with the intracellular domain of TLR4 and activation of downstream NF-κB signaling. Celastrol can bind to MD2 and disrupt the interaction of PA and MD2 and therefore inhibit the NF-κB signaling and protect against insulin resistance (color online).