title: Anti-obesity phenotypic screening looking to increase OBR cell surface expression.
abstract: The leptin receptor, OBR, is involved in the regulation of whole-body energy homeostasis. Most obese people are resistant to leptin and do not respond to the hormone. The prevention and reversal of leptin resistance is one of the major current goals of obesity research. We showed previously that increased OBR cell surface expression concomitantly increases cellular leptin signaling and prevents obesity development in mice. Improvement of OBR cell surface expression can thus be considered as an interesting anti-obesity therapeutic strategy. To identify compounds that increase the surface expression of OBR, we developed a cell-based, phenotypic assay to perform a high-content screen (HCS) against a library of 50,000 chemical compounds. We identified 67 compounds that increased OBR cell surface expression with AC50 values in the low micromolar range and no effect on total OBR expression and cellular toxicity. Compounds were classified into 16 chemical clusters, of which 4 potentiated leptin-promoted signaling through the JAK2/STAT3 pathway. In conclusion, development of a robust phenotypic screening approach resulted in the discovery of four new scaffolds that demonstrate the desired biological activity and could constitute an original therapeutic solution against obesity and associated disorders.
authors: 1IPK, Seongnam-si, South Korea.
authors: Tae-Hee
authors: TH
authors: Kim
authors: Dong-Hwa
authors: DH
authors: Choi
authors: Virginie
authors: V
authors: Vauthier
authors: Julie
authors: J
authors: Dam
authors: Xiaolan
authors: X
authors: Li
authors: Yeon-Ju
authors: YJ
authors: Nam
authors: YoonAe
authors: Y
authors: Ko
authors: Ho Jeong
authors: HJ
authors: Kwon
authors: Sang Hoon
authors: SH
authors: Shin
authors: Jonathan
authors: J
authors: Cechetto
authors: Veronica
authors: V
authors: Soloveva
authors: Ralf
authors: R
authors: Jockers
mesh_terms: D002460:Cell Line; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D015870:Gene Expression; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays; D006801:Humans; D009765:Obesity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries
chemical_list: D054411:Receptors, Leptin; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries
keywords: OBR; high-content screening; leptin receptor; obesity; phenotypic screening