Anti-obesity phenotypic screening looking to increase OBR cell surface expression

Tae Hee Kim, Dong Hwa Choi, Virginie Vauthier, Julie Dam, Xiaolan Li, Yeon Ju Nam, Yoonae Ko, Ho Jeong Kwon, Sang Hoon Shin, Jonathan Cechetto, Veronica Soloveva, Ralf Jockers

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)88-99
Number of pages12
JournalJournal of Biomolecular Screening
Volume19
Issue number1
DOIs
Publication statusPublished - 2014 Jan

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Biotechnology
  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

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  • Cite this

    Kim, T. H., Choi, D. H., Vauthier, V., Dam, J., Li, X., Nam, Y. J., Ko, Y., Kwon, H. J., Shin, S. H., Cechetto, J., Soloveva, V., & Jockers, R. (2014). Anti-obesity phenotypic screening looking to increase OBR cell surface expression. Journal of Biomolecular Screening, 19(1), 88-99. https://doi.org/10.1177/1087057113499185