Adipose Tissue Metabolic Function and Dysfunction: Impact of Burn Injury

For decades, adipose tissue had been considered as merely a storage depot and cushion to protect organs against trauma and injury. However, in recent years, a number of impactful studies have pinpointed the adipose tissue as an endocrine organ mediating systemic dysfunction in not only metabolic disorders such as obesity, but also in the stages following traumatic events such as severe burns. For instance, thermal injury induces a chronic β-adrenergic response associated with drastic increases in adipose lipolysis, macrophage infiltration and IL-6 mediated browning of white adipose tissue (WAT). The downstream consequences of these physiological changes to adipose, such as hepatomegaly and muscle wasting, are only now coming to light and suggest that WAT is both a culprit in and initiator of metabolic disorders after burn injury. To that effect, the aim of this review is to chronicle and critically analyze the scientific advances made in the study of adipose tissue with regards to its role in orchestrating the hypermetabolic response and detrimental effects of burn injury. The topics covered include the magnitude of the lipolytic response following thermal trauma and how WAT browning and inflammation perpetuate this cycle as well as how WAT physiology impacts insulin resistance and hyperglycemia post-burn. To conclude, we discuss how these findings can be translated from bench to bedside in the form of therapeutic interventions which target physiological changes to WAT to restore systemic homeostasis following a severe burn.

[1]  N. Bhattarai,et al.  Brown adipose tissue recruitment in a rodent model of severe burns. , 2020, Burns : journal of the International Society for Burn Injuries.

[2]  M. V. van Baar,et al.  Burn injury , 2020, Nature Reviews Disease Primers.

[3]  Sheri Barke Glycemic index , 2020, Definitions.

[4]  M. Jeschke,et al.  Inhibition of Lipolysis with Acipimox Attenuates Post-Burn White Adipose Tissue Browning and Hepatic Fat Infiltration. , 2020, Shock.

[5]  M. Jeschke,et al.  Browning of white adipose tissue after a burn injury promotes hepatic steatosis and dysfunction , 2019, Cell Death & Disease.

[6]  M. Jeschke,et al.  NLRP3 Inflammasome Mediates White Adipose Tissue Browning After Burn. , 2019, American journal of physiology. Endocrinology and metabolism.

[7]  M. Fear,et al.  Understanding acute burn injury as a chronic disease , 2019, Burns & trauma.

[8]  M. Jeschke,et al.  Metformin prevents the pathological browning of subcutaneous white adipose tissue , 2019, Molecular metabolism.

[9]  P. Scherer,et al.  Adipogenesis and metabolic health , 2019, Nature Reviews Molecular Cell Biology.

[10]  M. Jeschke,et al.  NLRP3 Inflammasome Modulates Post-Burn Lipolysis and Hepatic Fat Infiltration via Fatty Acid Synthase , 2018, Scientific Reports.

[11]  S. Kajimura,et al.  The Common and Distinct Features of Brown and Beige Adipocytes , 2018, Trends in Endocrinology & Metabolism.

[12]  P. Scherer,et al.  Immunologic and endocrine functions of adipose tissue: implications for kidney disease , 2018, Nature Reviews Nephrology.

[13]  M. Jeschke,et al.  Taming the Flames: Targeting White Adipose Tissue Browning in Hypermetabolic Conditions , 2017, Endocrine reviews.

[14]  M. Jeschke,et al.  The biochemical alterations underlying post-burn hypermetabolism. , 2017, Biochimica et biophysica acta. Molecular basis of disease.

[15]  M. Jeschke,et al.  Alternatively Activated Macrophages Drive Browning of White Adipose Tissue in Burns , 2017, Annals of surgery.

[16]  J. Awika,et al.  A role for PFKFB3/iPFK2 in metformin suppression of adipocyte inflammatory responses. , 2017, Journal of molecular endocrinology.

[17]  M. Jeschke,et al.  Glucose Control in Severely Burned Patients Using Metformin: An Interim Safety and Efficacy Analysis of a Phase II Randomized Controlled Trial , 2016, Annals of surgery.

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

[19]  M. Jeschke,et al.  Pathophysiologic Response to Burns in the Elderly , 2015, EBioMedicine.

[20]  M. Fasshauer,et al.  Adipokines in health and disease. , 2015, Trends in pharmacological sciences.

[21]  R. Bergman,et al.  Lipid-induced insulin resistance does not impair insulin access to skeletal muscle. , 2015, American journal of physiology. Endocrinology and metabolism.

[22]  A. Grefhorst,et al.  Estrogens increase expression of bone morphogenetic protein 8b in brown adipose tissue of mice , 2015, Biology of Sex Differences.

[23]  L. Sidossis,et al.  Chronic Adrenergic Stress Causes Adrenergic β‐3 Receptor Up‐regulation in White Adipose Tissue of Burn Patients , 2015 .

[24]  F. Wondisford,et al.  Metformin action: concentrations matter. , 2015, Cell metabolism.

[25]  H. Münzberg,et al.  Leptin and Insulin Act on POMC Neurons to Promote the Browning of White Fat , 2015, Cell.

[26]  Antonio Vidal-Puig,et al.  The different shades of fat , 2014, Nature.

[27]  M. Jeschke,et al.  Leukocyte Infiltration and Activation of the NLRP3 Inflammasome in White Adipose Tissue Following Thermal Injury* , 2014, Critical care medicine.

[28]  N. Møller,et al.  Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease. , 2014, Journal of molecular endocrinology.

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

[30]  K. Bae,et al.  Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells. , 2014, World journal of stem cells.

[31]  D. Herndon,et al.  Is propranolol of benefit in pediatric burn patients? , 2013, Advances in surgery.

[32]  P. Scherer,et al.  Tracking adipogenesis during white adipose tissue development, expansion and regeneration , 2013, Nature Medicine.

[33]  H. Almeida,et al.  Alpha-MSH signalling via melanocortin 5 receptor promotes lipolysis and impairs re-esterification in adipocytes. , 2013, Biochimica et biophysica acta.

[34]  T. Rülicke,et al.  Bi-directional interconversion of brite and white adipocytes , 2013, Nature Cell Biology.

[35]  R. Tompkins,et al.  Brown adipose tissue and its modulation by a mitochondria-targeted peptide in rat burn injury-induced hypermetabolism. , 2013, American journal of physiology. Endocrinology and metabolism.

[36]  Teresa Oliveira,et al.  Biochemistry of adipose tissue: an endocrine organ , 2013, Archives of medical science : AMS.

[37]  T. Endo,et al.  Expression of functional TSH receptor in white adipose tissues of hyt/hyt mice induces lipolysis in vivo. , 2012, American journal of physiology. Endocrinology and metabolism.

[38]  B. Spiegelman,et al.  FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. , 2012, Genes & development.

[39]  R. Locksley,et al.  Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis , 2011, Nature.

[40]  R. Tompkins,et al.  Association of Heat Production with 18F-FDG Accumulation in Murine Brown Adipose Tissue After Stress , 2011, The Journal of Nuclear Medicine.

[41]  R. Tompkins,et al.  Effects of burn injury, cold stress and cutaneous wound injury on the morphology and energy metabolism of murine brown adipose tissue (BAT) in vivo. , 2011, Life sciences.

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

[43]  Биология Alpha-2 Adrenergic Receptor , 2010 .

[44]  D. Herndon,et al.  Intensive insulin therapy in severely burned pediatric patients: a prospective randomized trial. , 2010, American journal of respiratory and critical care medicine.

[45]  D. Langin,et al.  Adipose tissue lipolysis , 2010, Current opinion in clinical nutrition and metabolic care.

[46]  K. Kristiansen,et al.  The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. , 2010, American journal of physiology. Endocrinology and metabolism.

[47]  D. Herndon,et al.  EXTENT AND MAGNITUDE OF CATECHOLAMINE SURGE IN PEDIATRIC BURNED PATIENTS , 2010, Shock.

[48]  A. Vidal-Puig,et al.  Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome--an allostatic perspective. , 2010, Biochimica et biophysica acta.

[49]  S. Grundy,et al.  Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International As , 2009, Circulation.

[50]  D. Langin,et al.  Lipolysis and lipid mobilization in human adipose tissue. , 2009, Progress in lipid research.

[51]  G. Hotamisligil,et al.  Mechanisms of TNF-alpha-induced insulin resistance. , 2009 .

[52]  D. Hatef,et al.  Pathophysiologic Response to Severe Burn Injury , 2009 .

[53]  Y. Zick,et al.  Phosphorylation of IRS proteins, insulin action, and insulin resistance. , 2009, American journal of physiology. Endocrinology and metabolism.

[54]  A. Vidal-Puig,et al.  Adipose tissue expandability: the metabolic problems of obesity may arise from the inability to become more obese. , 2008, Biochemical Society transactions.

[55]  D. Chinkes,et al.  Pathophysiologic Response to Severe Burn Injury , 2008, Annals of surgery.

[56]  B. Spiegelman,et al.  PRDM16 controls a brown fat/skeletal muscle switch , 2008, Nature.

[57]  E. Blaak,et al.  Catecholamine-induced lipolysis in adipose tissue and skeletal muscle in obesity , 2008, Physiology & Behavior.

[58]  A. Vidal-Puig,et al.  Thematic review series: Adipocyte Biology. Adipose tissue function and plasticity orchestrate nutritional adaptation Published, JLR Papers in Press, March 20, 2007. , 2007, Journal of Lipid Research.

[59]  N. Møller,et al.  Dose-response effects of free fatty acids on glucose and lipid metabolism during somatostatin blockade of growth hormone and insulin in humans. , 2007, The Journal of clinical endocrinology and metabolism.

[60]  Jan Nedergaard,et al.  Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages , 2007, Proceedings of the National Academy of Sciences.

[61]  S. Grinspoon,et al.  Improved triglycerides and insulin sensitivity with 3 months of acipimox in human immunodeficiency virus-infected patients with hypertriglyceridemia. , 2006, The Journal of clinical endocrinology and metabolism.

[62]  R. Barrow,et al.  The Use of Beta-Adrenergic Blockade in Preventing Trauma-Induced Hepatomegaly , 2006, Annals of surgery.

[63]  D. Yoon,et al.  Signaling pathways implicated in α‐melanocyte stimulating hormone‐induced lipolysis in 3T3‐L1 adipocytes , 2005, Journal of cellular biochemistry.

[64]  R. DeFronzo,et al.  Dose-response effect of elevated plasma free fatty acid on insulin signaling. , 2005, Diabetes.

[65]  G. Wilcox Insulin and insulin resistance. , 2005, The Clinical biochemist. Reviews.

[66]  R. Wolfe,et al.  Influence of Metformin on Glucose Intolerance and Muscle Catabolism Following Severe Burn Injury , 2005, Annals of surgery.

[67]  Frank Eisenhaber,et al.  Fat Mobilization in Adipose Tissue Is Promoted by Adipose Triglyceride Lipase , 2004, Science.

[68]  S. Collins,et al.  Beta-adrenergic receptors and regulation of energy expenditure: a family affair. , 2004, Annual review of pharmacology and toxicology.

[69]  K. Frayn,et al.  Adipose tissue as a buffer for daily lipid flux , 2002, Diabetologia.

[70]  U. Smith Impaired (‘diabetic’) insulin signaling and action occur in fat cells long before glucose intolerance—is insulin resistance initiated in the adipose tissue? , 2002, International Journal of Obesity.

[71]  R. Zechner,et al.  Hormone-sensitive Lipase Deficiency in Mice Causes Diglyceride Accumulation in Adipose Tissue, Muscle, and Testis* , 2002, The Journal of Biological Chemistry.

[72]  Y. Kido,et al.  The Insulin Receptor and Its Cellular Targets , 2001 .

[73]  M. White,et al.  IRS proteins and beta-cell function. , 2001, Diabetes.

[74]  R. Ahima,et al.  Adipose Tissue as an Endocrine Organ , 2006, Obesity.

[75]  W. L. Lin,et al.  Changes in serum tumour necrosis factor-α in burned patients , 1997 .

[76]  M. Berlan,et al.  In situ assessment of the role of the β1, β2‐ and β3‐adrenoceptors in the control of lipolysis and nutritive blood flow in human subcutaneous adipose tissue , 1996 .

[77]  G. Schultz,et al.  The human thyrotropin receptor: a heptahelical receptor capable of stimulating members of all four G protein families. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[78]  M Lafontan,et al.  Fat cell adrenergic receptors and the control of white and brown fat cell function. , 1993, Journal of lipid research.

[79]  R. Wolfe,et al.  Effect of severe burn injury on substrate cycling by glucose and fatty acids. , 1987, The New England journal of medicine.

[80]  R. Wolfe,et al.  Regulation of Lipolysis in Severely Burned Children , 1987, Annals of surgery.

[81]  P. Belfrage,et al.  Hormone-sensitive lipase and monoacylglycerol lipase are both required for complete degradation of adipocyte triacylglycerol. , 1986, Biochimica et biophysica acta.

[82]  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.

[83]  J. Heeren,et al.  Adipose tissue browning and metabolic health , 2014, Nature Reviews Endocrinology.

[84]  G. Ashcroft,et al.  Tumor necrosis factor‐alpha (TNF‐α) is a therapeutic target for impaired cutaneous wound healing , 2012, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[85]  M. Jensen,et al.  Insulin dose response analysis of free fatty acid kinetics. , 2007, Metabolism: clinical and experimental.

[86]  Y. Kido,et al.  Clinical review 125: The insulin receptor and its cellular targets. , 2001, The Journal of clinical endocrinology and metabolism.

[87]  C. Bellone,et al.  ON A ROLE , 1996 .

[88]  M. Berlan,et al.  The alpha 2-adrenergic receptor of human fat cells: comparative study of alpha 2-adrenergic radioligand binding and biological response. , 1982, Journal de physiologie.

[89]  Y. Matsuhara [Hormone sensitive lipase]. , 1970, Nihon Naibunpi Gakkai zasshi.