Transcriptomics-driven drug screening identifies BRD-K78062244 in promoting white adipose tissue browning

Area of Science:

• Metabolic Research
• Pharmacology
• Genomics

Background:

• Obesity and related diseases pose global health challenges.
• White adipose tissue (WAT) browning increases energy expenditure, offering a therapeutic target for obesity.
• Current drug screening methods are limited by complex signaling pathways involved in WAT browning.

Purpose of the Study:

• To develop a novel, cross-species strategy for identifying compounds that promote WAT browning.
• To establish a reliable gene signature for adipose browning.
• To validate candidate compounds for their potential in metabolic remodeling.

Main Methods:

• Integrated human and mouse single-nucleus and bulk RNA sequencing data.
• Constructed a "white adipose tissue browning-associated gene" (WAT-BAG) signature.
• Utilized the Connectivity Map (CMap) database for compound screening.
• Performed in vitro and in vivo functional validation of candidate compounds.

Main Results:

• Identified a cross-species gene set (WAT-BAG) for adipose browning.
• Screened compounds using WAT-BAG and CMap, identifying BRD-K78062244 as a top candidate.
• BRD-K78062244 promoted WAT-to-BAT transition, activated the PPAR signaling pathway, and inhibited lipid accumulation in vitro.
• In vivo studies showed BRD-K78062244 improved glucose handling and enhanced thermogenesis in mice.

Conclusions:

• A transcriptome-guided drug discovery strategy was successfully developed for identifying WAT browning promoters.
• BRD-K78062244 demonstrates significant potential for metabolic remodeling and obesity treatment.
• The study provides a new framework for discovering compounds targeting WAT browning using multi-omics data.