Metabolomic and molecular pathway analysis reveal metabolic pathways by which propranolol improves outcomes of severely burned patients
Sarah Rehou1, Lauar De Brito Monteiro1, Christopher Auger2, Carly Knuth3, Abdikarim Abdullahi3, Marc G. Jeschke*1
1Surgery, McMaster University and HHSC, Hamilton, ON, Canada; 2Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; 3Institue of Medical Science, University of Toronto, Toronto, ON, Canada
Background: Several studies indicated that propranolol, a non-selective beta receptor blocker, improves outcomes of severely burned patients. While the clinical and physiological benefits of beta blockade are well characterized the underlying metabolic mechanisms are less well defined. We hypothesized that propranolol improves post burn outcomes by profoundly modulating essential systemic and adipose metabolic pathways. Methods: In this phase II randomized controlled trial, patients with burns ≥20% total body surface area were randomly assigned to control or propranolol (dose given to decrease heart rate <100 bpm). Outcomes included clinical markers, systemic inflammatory and lipidomic profile, untargeted metabolomics as well as molecular pathways. Results: Fifty-two severely burned patients were enrolled in this trial (propranolol n=23 and controls n=29). There were no significant differences in demographics or injury severity between groups. Metabolomic pathway analyses of the adipose tissue showed that propranolol substantially alters and “normalizes� several essential metabolic pathways involved in energy metabolism (NAD+/NADH ratio, amino acid metabolism, and mitochondrial health), nucleotide metabolism, and catecholamine degradation, Figure 1 (p<0.05). Lipidomic analysis revealed that propranolol-treated patients had lower levels of pro-inflammatory palmitic acid (p<0.05) and saturated fatty acids in general (p<0.05) with an increased ratio of polyunsaturated fatty acids (p<0.05), thus shifting the lipidomic profile towards an anti-inflammatory phenotype after burn (p<0.05). On a molecular level these metabolic effects were mediated by decreased activation of hormone-sensitive lipase at serine 660 (p<0.05) leading to decreased adipose tissue lipolysis, significantly lower UCP-1 expression and adipose tissue browning, significantly reduced ER stress by decreasing p-JNK (p<0.05) and significantly improving mitochondrial respiration and function (p<0.05). Corroborating the metabolomic results, we found that propranolol normalized post-burn insulin resistance and significantly improved glucose metabolism (p<0.05). Conclusions: We propose that propranolol’s ability to mitigate pathophysiological changes to essential metabolic pathways results in significantly improved overall inflammatory and physiologic responses which are associated with improved outcomes after burn.
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