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

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.