2. Academic Validation
  3. Isomeranzin activates Gnas-AMPK signaling to drive white adipose browning and curb obesity in mice

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

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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