Hypermetabolism is a state of markedly elevated resting energy expenditure, and is characterized by metabolic imbalance, reflected in abnormal accumulation of circulating energy substrates such as free fatty acids and uncontrolled catabolism in adipose tissue and skeletal muscle. These alterations lead to systemic metabolic dysfunction, exacerbated inflammation, multiple organ failure, and poor clinical outcomes.

A key driver of the hypermetabolic state post-burn is the "browning" of white adipose tissue. Although UCP1-mediated thermogenesis is crucial for adaptive thermoregulation, its pathological activation after burns leads to excessive metabolic consumption. Studies have shown that this process is promoted by bone marrow-derived interleukin-6 (IL-6). This white adipose tissue browning is further associated with burn-induced hepatic steatosis.

In a study published in Cell Reports on Nov. 18, a team led by Prof. CHEN Yan from the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences discovered that blocking glycogen synthase 1 (GYS1) increases uridine diphosphate glucose (UDPG) which directly binds to JAK2 protein, inhibiting IL-6 induced JAK2-STAT3 signaling post-burn injury, which suppresses thermogenesis in white adipose tissue and ameliorates the body's hypermetabolic state. 

GYS1 is involved in glycogen synthesis. Previous studies have showed that adipose tissue-specific knockout of Gys1 gene attenuated the browning response under cold or β3-adrenergic agonist stimulation. However, the role of GYS1 in burn-induced white adipose tissue browning remains unknown.

In this study, researchers found that GYS1 expression was significantly upregulated in the white adipose tissue of both mice and humans after burn injury. Adipose tissue-specific Gys1 knockout effectively suppressed burn-induced white adipose tissue browning and lipolysis, improved hepatic steatosis, and significantly increased survival rates. Notably, Gys1 knockout did not affect the normal thermogenic function of brown adipose tissue nor did it alleviate muscle wasting.

Moreover, researchers found that Gys1 deletion led to substantial intracellular accumulation of UDPG. This accumulated UDPG effectively inhibited IL-6-induced JAK2-STAT3 signaling pathway activation through a unique mechanism independent of the β3-adrenergic or P2Y14 receptor pathways. Molecular docking and surface plasmon resonance experiments confirmed a direct and specific binding interaction between UDPG and the JAK2 protein.

Furthermore, researchers administered MZ-101, a specific small-molecule inhibitor of GYS1, for burn treatment, which successfully replicated the effects of genetic knockout, significantly elevating UDPG levels in adipose tissue, recapitulating various phenotypic improvements including suppressed white adipose tissue browning and improved hepatic steatosis, and ultimately enhancing the survival rate of the experimental burn animals.

This study systematically elucidates the regulatory role of the GYS1-UDPG-JAK2-STAT3 signaling axis in pathological white adipose tissue browning post-burn injury, which deepens the understanding of the mechanisms underlying post-burn metabolic disorders. It also proposes that the targeted inhibition of GYS1 could be a novel therapeutic strategy for treating burn-induced hypermetabolism, providing a potential therapeutic target for clinical intervention.