2. Academic Validation
  3. Blocking glycogen synthase 1 in white adipose tissue alleviates hypermetabolism following severe burn injury through inhibition of JAK2 by UDPG

Blocking glycogen synthase 1 in white adipose tissue alleviates hypermetabolism following severe burn injury through inhibition of JAK2 by UDPG

  • Cell Rep. 2025 Nov 18;44(12):116577. doi: 10.1016/j.celrep.2025.116577.
Shixuan Zhuo 1,  Zinan Wang 1,  Lanzexin Yang 1,  Yixuan Yuan 2,  Dahai Hu 2,  Yan Chen 3
Affiliations

Affiliations

  • 1 Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 2 Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
  • 3 Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: [email protected].
PMID: 41259203 DOI: 10.1016/j.celrep.2025.116577
Abstract

Browning of white adipose tissue (WAT) contributes to the sustained hypermetabolism observed in patients with burns. How glycogen metabolism in WAT is linked to burn-induced hypermetabolism remains unknown. We discover that burn-induced UCP1 expression in subcutaneous WAT is accompanied by elevation of glycogen synthase 1 (GYS1). Adipose tissue-specific deletion of Gys1 suppresses burn-induced UCP1 expression. Gys1 deletion inhibits WAT lipolysis and mitigates hepatic steatosis. Mechanistically, the effects of Gys1 deletion on burn-induced hypermetabolism are mediated by an increase in uridine diphosphate glucose (UDPG), the substrate of GYS1. Both Gys1 deletion and UDPG administration attenuate signaling of interleukin-6. UDPG directly interacts with JAK2 and inhibits STAT3 phosphorylation. Administration of MZ-101, a small-molecule inhibitor of GYS1, suppresses post-burn hypermetabolism and improves the survival rate of mice. Our findings uncover the regulatory role of the GYS1-UDPG-JAK2-STAT3 cascade in WAT during post-burn hypermetabolism and underscore the potential of GYS1 inhibition as a therapeutic strategy for burn injury.

Keywords

CP: immunology; CP: metabolism; GYS1; JAK2; UCP1; UDPG; browning of white adipose tissue; burn; cachexia; glycogen synthesis; hypermetabolism; interleukin-6.

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