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Published on: July 17, 2018
Anti-obesity phenotypic screening looking to increase OBR cell surface expression
Tae-Hee Kim1, Dong-Hwa Choi, Virginie Vauthier
11IPK, Seongnam-si, South Korea.
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.
Insights
Researchers identified compounds that increase leptin receptor (OBR) cell surface expression, a potential strategy to combat obesity by improving leptin signaling and overcoming leptin resistance.
Area of Science:
- Metabolism and Endocrinology
- Pharmacology
- Obesity Research
Background:
- Leptin receptor (OBR) regulates energy homeostasis, but leptin resistance is common in obesity.
- Increased OBR cell surface expression enhances leptin signaling and prevents obesity in preclinical models.
- Targeting OBR expression is a promising anti-obesity therapeutic strategy.
Purpose of the Study:
- To discover novel compounds that enhance OBR cell surface expression.
- To identify chemical scaffolds with anti-obesity potential.
- To develop a high-content screening assay for OBR modulators.
Main Methods:
- Developed a cell-based phenotypic assay for high-content screening (HCS).
- Screened a library of 50,000 chemical compounds.
- Validated hits for OBR surface expression, total OBR levels, and cellular toxicity.
Main Results:
- Identified 67 compounds increasing OBR cell surface expression (low micromolar AC50).
- No observed effects on total OBR expression or significant cellular toxicity.
- Four distinct chemical clusters potentiated JAK2/STAT3 signaling, indicating biological activity.
Conclusions:
- A robust phenotypic screening approach successfully identified novel OBR-targeting compounds.
- Four new chemical scaffolds demonstrate potential as therapeutic agents against obesity.
- These findings offer an original therapeutic avenue for obesity and related disorders.
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