2025/11/26 by M. Shi, Yinsong Ye, Lizhi Hu +9 · 1 voice
Medicine · Neuroscience · #Adipokines, Inflammation, and Metabolic Diseases #Adipose Tissue and Metabolism #Regulation of Appetite and Obesity
paper · doi:10.1038/s44321-025-00335-y
openalex publication_date 2025/11/26 · openalex created_date 2025/11/27 · openalex updated_date 2026/07/28
Obesity is a major global health challenge, and promoting the browning of white adipose tissue (WAT) represents a promising therapeutic strategy. However, pharmacological approaches to induce adipose thermogenesis remain limited. Through a Connectivity Map-based screen, we identified isomeranzin (ISM) as a potent small-molecule activator of WAT browning. ISM enhances thermogenesis in adipocytes by activating the AMP-activated protein kinase (AMPK) pathway. Integrated limited proteolysis-mass spectrometry, cellular thermal shift assays, and molecular docking identified guanine nucleotide-binding protein G(s) alpha subunit (Gnas) as the direct binding target of ISM. Mechanistic studies further revealed that ISM induces WAT browning through the Gnas-dependent activation of cAMP-AMPK signaling cascade. These findings elucidate the molecular mechanism underlying ISM activity and highlight its potential as a lead compound for enhancing energy expenditure and combating obesity.