Subcutaneous white adipose tissue independently regulates burn-induced hypermetabolism via immune-adipose crosstalk.

Severe burns induce a chronic hypermetabolic state that persists well past wound closure, indicating that additional internal mechanisms must be involved. Adipose tissue is suggested to be a central regulator in perpetuating hypermetabolism, although this has not been directly tested. Here, we show that thermogenic adipose tissues are activated in parallel to increases in hypermetabolism independent of cold stress. Using an adipose tissue transplantation model, we discover that burn-derived subcutaneous white adipose tissue alone is sufficient to invoke a hypermetabolic response in a healthy recipient mouse. Concomitantly, transplantation of healthy adipose tissue alleviates metabolic dysfunction in a burn recipient. We further show that the nicotinic acetylcholine receptor signaling pathway may mediate an immune-adipose crosstalk to regulate adipose tissue remodeling post-injury. Targeting this pathway could lead to innovative therapeutic interventions to counteract hypermetabolic pathologies.

Single-nuclei RNA Profiling Reveals Disruption of Adipokine and Inflammatory Signaling in Adipose Tissue of Burn Patients.

OBJECTIVE: We conducted a large-scale investigation of the systemic and adipose tissue-specific alterations in a clinical population of burn patients to identify factors that may influence hypermetabolism. BACKGROUND: Previous research has identified chronic disturbances in adipose tissue inflammation, lipolysis, and browning, which may drive the perpetuation of hypermetabolism following the severe adrenergic stress of a burn injury. Given that adipose tissue is thought to be a central node in the regulation of systemic metabolism, we believe that systematically delineating the pathologic role of adipose tissue postburn, will lead to the identification of novel interventions to mitigate morbidity and mortality from severe burns. METHODS: This was a single-institution cohort study, which obtained plasma and subcutaneous adipose tissue samples from severely burn adult patients over various time points during acute hospitalization. Whole-body clinical, metabolic, and inflammatory mediators were assessed in plasma, while genetic analyses through RT-qPCR and single-nuclei RNA sequencing were conducted in adipose tissue. RESULTS: Systemic inflammation and adrenergic stress increase IL-6 signaling, lipolysis, browning, and adipokine dysfunction in the adipose tissue of adult burn patients, which may further propagate the long-term hypermetabolic response. Moreover, using single-nuclei RNA sequencing, we provide the first comprehensive characterization of alterations in the adipose tissue microenvironment occurring at acute and chronic stages postburn. CONCLUSION: We provide novel insight toward the effect of burns on adipokine release, inflammatory signaling pathways, and adipose heterogeneity over the trajectory of acute and chronic stages.