Leptin sensitizer reverses obesity (original) (raw)

Metabolic disease

Nature Reviews Drug Discovery volume 15, page 601 (2016)Cite this article

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Increased endoplasmic reticulum (ER) stress in hypothalamic neurons has a key role in the development of leptin resistance and obesity. Previously, the authors searched the Broad Institute Connectivity Map (CMAP) database for small molecules with gene expression signatures similar to those of models of ER stress and leptin resistance reversal in the mouse liver and hypothalamus. This led to the identification of celastrol as a potent leptin sensitizer. The authors therefore set out to determine whether the gene expression profile of celastrol itself could be used to identify novel leptin sensitizers.

To do this, they analysed microarray data from mouse embryonic fibroblasts treated with vehicle or celastrol, and created a gene expression signature comprising the 20 most upregulated and the 20 most downregulated genes by celastrol. Querying the CMAP database with this signature identified withaferin A (a steroidal lactone derived from the medicinal plant Withania somnifera) as one of the top-ranking chemical compounds, exhibiting a gene expression profile highly similar to that of celastrol. Analysis of microarray data from celastrol- and withaferin-A-treated DIO mice showed a high degree of similarity between the hypothalamic gene expression profiles.

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Crunkhorn, S. Leptin sensitizer reverses obesity.Nat Rev Drug Discov 15, 601 (2016). https://doi.org/10.1038/nrd.2016.166

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