Sepsis-Induced Increases in Inflammatory Mediators Associated with Adipose Tissue Browning in Burn Patients

Author(s):
Carly Knuth; Chris Auger; Sarah Rehou; Marc Jeschke

Background:

Burn injury and sepsis have been independently shown to trigger a drastic hypermetabolic response. We have previously shown that burn-induced hypermetabolism promotes a systemic inflammatory response mediated by IL-6 signalling, inducing the browning of white adipose tissue (WAT). Browning is characterized by white adipocytes adopting a brown-like phenotype, which is suggested to further propagate metabolic overdrive in burn patients. Whether sepsis contributes to IL-6-mediated WAT browning following burn injury remains unclear.

Hypothesis:

Given that the presence of sepsis further enhances the hypermetabolic response in burn patients, we hypothesize that IL-6-mediated WAT browning will be exacerbated in septic burn patients.

Methods:

Non-septic (n=58) and septic (n=48) adults with burns over 20% TBSA admitted between 2010-2015 were enrolled in this prospective study. Demographics, injury characteristics, clinical outcomes, resting energy expenditure (REE), and blood samples were obtained throughout hospitalization. Data was stratified based on date of collection into four groups: 0—7 days, 8—14days, 15—30 days, and >30days.

Results:

There were no differences in age (p=0.24), gender (p=0.29), TBSA (p=0.46), BMI (p=0.14), or baux score (p=0.28) between septic and non-septic patients. The average sepsis date of onset was approximately 13 days post-burn, which was accompanied by a signal towards an increase in predicted REE percentage at 8—14 days (p=0.07) in comparison to non-septic burn patients and significant reductions (p<0.05) in non-esterified fatty acids when comparing pre-septic and post-septic serum concentrations. Additionally, cyto/chemokines TNF-α (p<0.05), IL-10 (p<0.01), IL-6 (p<0.01) and MCP-1 (p<0.01) were significantly elevated in septic patients at 8—14 days post-burn compared to their non-septic counterparts. Notably, IL-6 (p<0.05) and MCP-1 (p<0.05) remained elevated until day 30 and beyond 30 days, respectively. IL-4 and IL-13 were significantly decreased (p<0.05) at 15—30 days compared to non-septic patients.

Conclusions:

Burn injury compounded by the presence of sepsis provokes an intensified hypermetabolic response, demonstrated by elevations in whole-body energy expenditure and reductions in free fatty acids, indicative of increases in lipid uptake. Additionally, pro-inflammatory cytokines were shown to significantly increase upon septic onset, while IL-4 and IL-13 were reduced in the days following septic onset. In support of previous work that determined IL-6 signalling, and not IL-4/13, mediate the hypermetabolic response of WAT browning in burn patients, we propose that the presence of sepsis contributes in an additive manner to the hypermetabolic condition.