Isomeranzin activates Gnas-AMPK signaling to drive white adipose browning and curb obesity in mice

  • EMBO Mol Med. 2025 Nov 26. doi: 10.1038/s44321-025-00335-y.
Menghao Shi  #  1  2 ,  Yinsong Ye  #  2  3 ,  Lizhi Hu  #  2  4  5 ,  Yibo Yan  2  3 ,  Shushu Jiang  1  2 ,  Pengchao Wang  1  2 ,  Fengcen Li  1  2 ,  Mingfa Ai  1  2 ,  Jinhui Huang  1  2 ,  Ling Yang  6  7  8 ,  Kai Huang  9  10  11 ,  Minglu Liang  12  13  14
Affiliations
  • 1. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3. Liyuan Cardiovascular Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4. Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, China.
  • 5. Hubei Clinical Research Center for Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, China.
  • 6. Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, China. [email protected].
  • 7. Hubei Clinical Research Center for Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, China. [email protected].
  • 8. Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 9. Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 10. Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, China. [email protected].
  • 11. Hubei Clinical Research Center for Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, China. [email protected].
  • 12. Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 13. Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, China. [email protected].
  • 14. Hubei Clinical Research Center for Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 41299101 DOI: 10.1038/s44321-025-00335-y
Abstract

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.

Keywords
AMPK; Adipose Browning; Gnas; Isomeranzin; Obesity.
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