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

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.