Activated Macrophages Drive Browning of WAT in Burns RESULTS Browning in Response to Burn Injury Is Associated With Increased Infiltration of Macrophages in the Adipose Burn Patients

Objective: The aim of this study was to uncover the mediators and mechanistic events that facilitate the browning of white adipose tissue (WAT) in response to burns. Background: In hypermetabolic patients (eg, burns, cancer), the browning of WAT has presented substantial clinical challenges related to cachexia, atherosclerosis, and poor clinical outcomes. Browning of the adipose tissue has recently been found to induce and sustain hypermetabolism. Although browning appears central in trauma-, burn-, or cancer-induced hypermetabolic catabolism, the mediators are essentially unknown. Methods: WAT and blood samples were collected from patients admitted to the Ross Tilley Burn Centre at Sunnybrook Hospital. Wild type, CCR2 KO, and interleukin (IL)-6 KO male mice were purchased from Jax laboratories and subjected to a 30% total body surface area burn injury. WAT and serum collected were analyzed for browning markers, macrophages, and metabolic state via histology, gene expression, and mitochondrial respiration. Results: In the present study, we show that burn-induced browning is associated with an increased macrophage infiltration, with a greater type 2 macrophage profile in the fat of burn patients. Similar to our clinical findings in burn patients, both an increase in macrophage recruitment and a type 2 macrophage profile were also observed in post burn mice. Genetic loss of the chemokine CCR2 responsible for macrophage migration to the adipose impairs burn-induced browning. Mechanistically, we show that macrophages recruited to burn-stressed subcutaneous WAT (sWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production mediated by IL-6, factors required for browning of sWAT. Conclusion: Together, our findings uncover macrophages as the key instigators and missing link in trauma-induced browning.

[1]  D. Colin,et al.  Caloric Restriction Leads to Browning of White Adipose Tissue through Type 2 Immune Signaling. , 2016, Cell metabolism.

[2]  M. Jeschke,et al.  White Adipose Tissue Browning: A Double-edged Sword , 2016, Trends in Endocrinology & Metabolism.

[3]  L. Sidossis,et al.  Brown Adipose Tissue Activation Is Linked to Distinct Systemic Effects on Lipid Metabolism in Humans. , 2016, Cell metabolism.

[4]  M. Jeschke.  Postburn Hypermetabolism: Past, Present, and Future , 2016, Journal of burn care & research : official publication of the American Burn Association.

[5]  Junichi Ishida,et al.  Hypermetabolism: should cancer types, pathological stages and races be considered in assessing metabolism and could elevated resting energy expenditure be the therapeutic target in patients with advanced cancer? , 2015, Journal of cachexia, sarcopenia and muscle.

[6]  M. Jeschke,et al.  Burn Induces Browning of the Subcutaneous White Adipose Tissue in Mice and Humans , 2015, Cell reports.

[7]  E. Wagner,et al.  A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. , 2014, Cell metabolism.

[8]  B. Spiegelman,et al.  Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia , 2014, Nature.

[9]  R. Palmiter,et al.  Eosinophils and Type 2 Cytokine Signaling in Macrophages Orchestrate Development of Functional Beige Fat , 2014, Cell.

[10]  L. Sidossis,et al.  Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress (1160.5) , 2014, Cell metabolism.

[11]  D. Herndon,et al.  Survivors Versus Nonsurvivors Postburn: Differences in Inflammatory and Hypermetabolic Trajectories , 2014, Annals of surgery.

[12]  Baocun Sun,et al.  Cold Exposure Promotes Atherosclerotic Plaque Growth and Instability via UCP1-Dependent Lipolysis , 2013, Cell metabolism.

[13]  Y. Tseng,et al.  Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. , 2013, The Journal of clinical investigation.

[14]  D. Herndon,et al.  Long-Term Persistance of the Pathophysiologic Response to Severe Burn Injury , 2011, PloS one.

[15]  F. Finkelman,et al.  Local Macrophage Proliferation, Rather than Recruitment from the Blood, Is a Signature of TH2 Inflammation , 2011, Science.

[16]  M. Karin,et al.  The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. , 2011, Cancer cell.

[17]  D. Cella,et al.  Muscle wasting in cancer cachexia: clinical implications, diagnosis, and emerging treatment strategies. , 2011, Annual review of medicine.

[18]  M. Jeschke.  The Hepatic Response to Thermal Injury: Is the Liver Important for Postburn Outcomes? , 2009, Molecular medicine.

[19]  C. Herder,et al.  Relationship between adipocyte size and adipokine expression and secretion. , 2007, The Journal of clinical endocrinology and metabolism.

[20]  S. Wigmore,et al.  Systemic inflammation, cachexia and prognosis in patients with cancer , 2005, Current opinion in clinical nutrition and metabolic care.

[21]  J. Bristow,et al.  RELATIVE HYPERMETABOLISM IN INFANTS WITH CONGENITAL HEART DISEASE AND UNDERNUTRITION. , 1965, Pediatrics.

[22]  M. Jeschke,et al.  IL-6 Signal From the Bone Marrow is Required for the Browning of White Adipose Tissue Post Burn Injury , 2017, Shock.

[23]  C. Ohlsson,et al.  Interleukin-6-deficient mice develop mature-onset obesity , 2002, Nature Medicine.