Advertisement

Molecular Medicine

, Volume 21, Issue 1, pp 959–968 | Cite as

Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury

  • Li Diao
  • David Patsouris
  • Ali-Reza Sadri
  • Xiaojing Dai
  • Saeid Amini-Nik
  • Marc G. Jeschke
Research Article

Abstract

Extensively burned patients often suffer from sepsis, a complication that enhances postburn hypermetabolism and contributes to increased incidence of multiple organ failure, morbidity and mortality. Despite the clinical importance of burn sepsis, the molecular and cellular mechanisms of such infection-related metabolic derangements and organ dysfunction are still largely unknown. We recently found that upon endoplasmic reticulum (ER) stress, the white adipose tissue (WAT) interacts with the liver via inflammatory and metabolic signals leading to profound hepatic alterations, including hepatocyte apoptosis and hepatic fatty infiltration. We therefore hypothesized that burn plus infection causes an increase in lipolysis of WAT after major burn, partially through induction of ER stress, contributing to hyperlipidemia and profound hepatic lipid infiltration. We used a two-hit rat model of 60% total body surface area scald burn, followed by intraperitoneal (IP) injection of Pseudomonas Aeruginosa-derived lipopolysaccharide (LPS) 3 d postburn. One day later, animals were euthanized and liver and epididymal WAT (EWAT) samples were collected for gene expression, protein analysis and histological study of inflammasome activation, ER stress, apoptosis and lipid metabolism. Our results showed that burn plus LPS profoundly increased lipolysis in WAT associated with significantly increased hepatic lipid infiltration. Burn plus LPS augmented ER stress by upregulating CHOP and activating ATF6, inducing NLRP3 inflammasome activation and leading to increased apoptosis and lipolysis in WAT with a distinct enzymatic mechanism related to inhibition of AMPK signaling. In conclusion, burn sepsis causes profound alterations in WAT and liver that are associated with changes in organ function and structure.

Notes

Acknowledgments

This research was supported by the National Institutes of Health (R01-GM087285-01), Canadian Institutes of Health Research (123336), the CFI Leaders Opportunity Fund (25407) and the Health Research Grant Program. We thank Cassandra Belo for her technical assistance and proofreading. We thank Abdikarim Abdullahi for his assistance in animal experiments. We are grateful to Sheila Costford for her final proofreading and editing of the manuscript.

Supplementary material

10020_2015_2101959_MOESM1_ESM.pdf (2.1 mb)
Supplementary material, approximately 2.14 MB.

References

  1. 1.
    Jeschke MG, et al. (2012) Severe injury is associated with insulin resistance, endoplasmic reticulum stress response, and unfolded protein response. Ann. Surg. 255:370–8.CrossRefGoogle Scholar
  2. 2.
    Jeschke MG, Boehning D. (2012) Endoplasmic reticulum stress and insulin resistance posttrauma: similarities to type 2 diabetes. J. Cell. Mol. Med. 16:437–44.CrossRefGoogle Scholar
  3. 3.
    Jeschke MG, et al. (2015) Morbidity and survival probability in burn patients in modern burn care. Crit. Care Med. 43:808–15.CrossRefGoogle Scholar
  4. 4.
    Jeschke MG, et al. (2014) Survivors versus non-survivors postburn: differences in inflammatory and hypermetabolic trajectories. Ann. Surg. 259:814–23.CrossRefGoogle Scholar
  5. 5.
    Herndon DN, Tompkins RG. (2004) Support of the metabolic response to burn injury. Lancet. 363:1895–902.CrossRefGoogle Scholar
  6. 6.
    Jeschke MG, et al. (2008) Pathophysiologic response to severe burn injury. Ann. Surg. 248: 387–401.CrossRefGoogle Scholar
  7. 7.
    Diao L, et al. (2014) Burn plus lipopolysaccharide augments endoplasmic reticulum stress and NLRP3 inflammasome activation and reduces PGC-1alpha in liver. Shock. 41:138–44.CrossRefGoogle Scholar
  8. 8.
    Jeschke MG. (2009) The hepatic response to thermal injury: is the liver important for postburn outcomes? Mol. Med. 15:337–51.CrossRefGoogle Scholar
  9. 9.
    Barrow RE, et al. (2005) Identification of factors contributing to hepatomegaly in severely burned children. Shock. 24:523–8.CrossRefGoogle Scholar
  10. 10.
    Glass CK, Olefsky JM. (2012) Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab. 15:635–45.CrossRefGoogle Scholar
  11. 11.
    Herndon DN, Wilmore DW, Mason AD Jr. (1978) Development and analysis of a small animal model simulating the human postburn hypermetabolic response. J. Surg. Res. 25:394–403.CrossRefGoogle Scholar
  12. 12.
    Jeschke MG, et al. (2011) Insulin protects against hepatic damage postburn. Mol. Med. 17:516–22.CrossRefGoogle Scholar
  13. 13.
    Zebisch K, Voigt V, Wabitsch M, Brandsch M. (2012) Protocol for effective differentiation of 3T3-L1 cells to adipocytes. Anal. Biochem. 425:88–90.CrossRefGoogle Scholar
  14. 14.
    Amini-Nik S, et al. (2014) Beta-catenin-regulated myeloid cell adhesion and migration determine wound healing. J. Clin. Invest. 124:2599–610.CrossRefGoogle Scholar
  15. 15.
    Arno AI, et al. (2014) Effect of human Wharton’s jelly mesenchymal stem cell paracrine signaling on keloid fibroblasts. Stem Cells Transi. Med. 3:299–307.CrossRefGoogle Scholar
  16. 16.
    Bogdanovic E, et al. (2015) Endoplasmic reticulum stress in adipose tissue augments lipolysis. J. Cell. Mol. Med. 19:82–91.CrossRefGoogle Scholar
  17. 17.
    Grisouard J, et al. (2012) Both inflammatory and classical lipolytic pathways are involved in lipopolysaccharide-induced lipolysis in human adipocytes. Innate Immun. 18:25–34.CrossRefGoogle Scholar
  18. 18.
    Han J, et al. (2013) ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15:481–90.CrossRefGoogle Scholar
  19. 19.
    Yu TS, et al. (2010) The cannabinoid receptor type 2 is time-dependently expressed during skeletal muscle wound healing in rats. Int. J. Legal Med. 124:397–404.CrossRefGoogle Scholar
  20. 20.
    Smith B, George J. (2009) Adipocyte-hepatocyte crosstalk and the pathogenesis of nonalcoholic fatty liver disease. Hepatology. 49:1765–7.CrossRefGoogle Scholar
  21. 21.
    Birkenfeld AL, et al. (2011) Influence of the hepatic eukaryotic initiation factor 2alpha (eIF2alpha) endoplasmic reticulum (ER) stress response pathway on insulin-mediated ER stress and hepatic and peripheral glucose metabolism. J. Biol. Chem. 286:36163–70.CrossRefGoogle Scholar
  22. 22.
    Bradbury MW. (2006) Lipid metabolism and liver inflammation. I. Hepatic fatty acid uptake: possible role in steatosis. Am. J. Physiol. Gastrointest. Liver Physiol. 290:G194–8.CrossRefGoogle Scholar
  23. 23.
    Baranowski M, Blachnio-Zabielska A, Zabielski P, Gorski J. (2008) Pioglitazone induces lipid accumulation in the rat heart despite concomitant reduction in plasma free fatty acid availability. Arch. Biochem. Biophys. 477:86–91.CrossRefGoogle Scholar
  24. 24.
    Kidani Y, Bensinger SJ. (2012) Liver X receptor and peroxisome proliferator-activated receptor as integrators of lipid homeostasis and immunity. Immunol. Rev. 249:72–83.CrossRefGoogle Scholar
  25. 25.
    Palasciano G, et al. (2007) Non-alcoholic fatty liver disease in the metabolic syndrome. Curr. Pharm. Des. 13:2193–8.CrossRefGoogle Scholar
  26. 26.
    Walley KR, et al. (2014) PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci. Transi. Med. 6:258ra143.CrossRefGoogle Scholar
  27. 27.
    Szalowska E, et al. (2011) Comparative analysis of the human hepatic and adipose tissue transcriptomes during LPS-induced inflammation leads to the identification of differential biological pathways and candidate biomarkers. BMC Med Genomics. 4:71.CrossRefGoogle Scholar
  28. 28.
    Lampidonis AD, Rogdakis E, Voutsinas GE, Stravopodis DJ. (2011) The resurgence of Hormone-Sensitive Lipase (HSL) in mammalian lipolysis. Gene. 477:1–11.CrossRefGoogle Scholar
  29. 29.
    Jaworski K, Sarkadi-Nagy E, Duncan RE, Ahmadian M, Sul HS. (2007) Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue. Am. J. Physiol. Gastrointest. Liver Physiol. 293:G1–4.CrossRefGoogle Scholar
  30. 30.
    Zechner R, et al. (2012) FAT SIGNALS—lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 15:279–91.CrossRefGoogle Scholar
  31. 31.
    Deng J, et al. (2012) Lipolysis response to endoplasmic reticulum stress in adipose cells. J. Biol. Chem. 287:6240–9.CrossRefGoogle Scholar
  32. 32.
    Yasuhara S, et al. (2006) Adipocyte apoptosis after burn injury is associated with altered fat metabolism. J. Burn Care Res. 27:367–76.CrossRefGoogle Scholar
  33. 33.
    Asai A, et al. (2007) Primary role of functional ischemia, quantitative evidence for the two-hit mechanism, and phosphodiesterase-5 inhibitor therapy in mouse muscular dystrophy. PLoS One. 2:e806.CrossRefGoogle Scholar
  34. 34.
    Siegel RM. (2006) Caspases at the crossroads of immune-cell life and death. Nat. Rev. Immunol. 6:308–17.CrossRefGoogle Scholar
  35. 35.
    Lamkanfi M, Kanneganti TD. (2010) Caspase-7: a protease involved in apoptosis and inflammation. Int. J. Biochem. Cell Biol. 42:21–4.CrossRefGoogle Scholar
  36. 36.
    Stanojcic M, et al. (2014) Leukocyte infiltration and activation of the NLRP3 inflammasome in white adipose tissue following thermal injury. Crit. Care Med. 42:1357–64.CrossRefGoogle Scholar
  37. 37.
    Franchi L, Eigenbrod T, Munoz-Planillo R, Nunez G. (2009) The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat. Immunol. 10:241–7.CrossRefGoogle Scholar
  38. 38.
    Martinon F, Mayor A, Tschopp J. (2009) The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27:229–65.CrossRefGoogle Scholar
  39. 39.
    Sasaki K, Yoshida H. (2015) Organelle autoregulation-stress responses in the ER, Golgi, mitochondria and lysosome. J. Biochem. 157:185–95.CrossRefGoogle Scholar
  40. 40.
    Benetti E, Chiazza F, Patel NS, Collino M. (2013) The NLRP3 Inflammasome as a novel player of the intercellular crosstalk in metabolic disorders. Mediators Inflamm. 2013:678627.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Schroder K, Zhou R, Tschopp J. (2010) The NLRP3 inflammasome: a sensor for metabolic danger? Science. 327:296–300.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2015

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Li Diao
    • 1
  • David Patsouris
    • 1
  • Ali-Reza Sadri
    • 1
  • Xiaojing Dai
    • 1
  • Saeid Amini-Nik
    • 1
    • 2
  • Marc G. Jeschke
    • 1
    • 2
    • 3
  1. 1.Sunnybrook Research InstituteTorontoCanada
  2. 2.Department of Surgery, Division of Plastic Surgery, Department of ImmunologyUniversity of TorontoTorontoCanada
  3. 3.Ross Tilley Burn Center, Sunnybrook Health Sciences CenterUniversity of TorontoTorontoCanada

Personalised recommendations