Abstract

Research Article

Role of toll-like receptors and their ligands in adipocyte secretion

A Mishra*, AV Shestopalov, AM Gaponov, IA Alexandrov and SA Roumiantsev

Published: 08 April, 2021 | Volume 5 - Issue 1 | Pages: 001-007

Background: Adipose tissue is one of the main sites of energy homeostasis that regulates whole body metabolism with the help of adipokines. Disruption in its proper functioning results in adipose tissue remodeling (primarily hypertrophy and hyperplasia) which directly influences the secretion of said adipokines. Obesity characterized as chronic low-grade inflammation of the adipose tissue is one such condition that has far reaching effects on whole body metabolism. Inflammation in turn results in immune cells infiltrating into the tissue and further promoting adipocyte dysfunction.

Purpose: In our study we explored this adipose tissue-innate immunity axis by differentiating adipose tissue derived stem cells (ADSCs) into white and beige adipocytes. We further stimulated our cultures with lipopolysaccharide (LPS), flagellin, or meteorin-like, glial cell differentiation regulator (METRNL) to trigger an inflammatory response. We then evaluated Toll-like receptor (TLR) mRNA expression and secretion of interleukin (IL-6), interleukin-8 (IL-8), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in these cultures.

Results: We found that TLR2 is the highest expressed receptor in adipocytes. Further, LPS and METRNL are strong activators of TLR2 in white and beigeBMP7(-) adipocytes. TLR4 was not significantly expressed in any of our cultures despite LPS stimulation. TLR9 expression is upregulated in ADSCs upon LPS and METRNL stimulation. IL-6 and IL-8 secretion is increased upon LPS stimulation in white adipocytes. METRNL activates both IL-6 and IL-8 expression in adipocyte cultures. Lastly, BDNF and NGF is secreted by all adipocyte cultures with beigeBMP7(-) and beigeBMP7(+) secreting slightly higher amounts in comparison to white adipocytes.

Conclusion: ADSCs and adipocytes alike are capable of expressing TLRs, but white adipocytes remain the highest expressing in both control and stimulated cultures. TLR2 is highly expressed in white and beige adipocytes whereas TLR4 showed no significant expression. LPS and METRNL trigger IL-6 and IL-8 secretion in adipocytes. Products of white adipocyte “browning” are capable of secreting higher amounts of BDNF and NGF in comparison to white adipocytes.

Read Full Article HTML DOI: 10.29328/journal.apb.1001012 Cite this Article Read Full Article PDF

Keywords:

Adipocytes; LPS; Flagellin; Meteorin-like peptide (METRNL); TLR; Inflammation

References

  1. Blüher M, Mantzoros CS. From leptin to other adipokines in health and disease: Facts and expectations at the beginning of the 21st century. Metabolism. 2015; 64: 131–145. PubMed: https://pubmed.ncbi.nlm.nih.gov/25497344/
  2. Villarroya J, Cereijo R, Villarroya F. An endocrine role for brown adipose tissue? Am J Physiol Endocrinol Metab. 2013; 305; E567-72. PubMed: https://pubmed.ncbi.nlm.nih.gov/23839524/
  3. Lundgren P, Thaiss CA. The microbiome-adipose tissue axis in systemic metabolism. Am J Physiol Gastrointest Liver Physiol. 2020; 318: G717-724. PubMed: https://pubmed.ncbi.nlm.nih.gov/32068441/
  4. Kane H, Lynch L. Innate Immune Control of Adipose Tissue Homeostasis. Trends Immunol. 2019; 40: 857–872. PubMed: https://pubmed.ncbi.nlm.nih.gov/31399336/
  5. Li ZY, Song J, Zheng SL, Fan MB, Guan YF, et al. Adipocyte Metrnl Antagonizes Insulin Resistance Through PPARγ Signaling. Diabetes. 2015; 64: 4011–4022. PubMed: https://pubmed.ncbi.nlm.nih.gov/26307585/
  6. Fain JN. Release of Interleukins and Other Inflammatory Cytokines by Human Adipose Tissue Is Enhanced in Obesity and Primarily due to the Nonfat Cells. Vitam Horm. 2006; 74: 443–477. PubMed: https://pubmed.ncbi.nlm.nih.gov/17027526/
  7. Fresno M, Alvarez R, Cuesta N. Toll-like receptors, inflammation, metabolism and obesity. Arch Physiol Biochem. 2011; 117: 151–164. PubMed: https://pubmed.ncbi.nlm.nih.gov/21599616/
  8. Zhang J, Diao B, Lin X, Xu J, Tang F. TLR2 and TLR4 mediate an activation of adipose tissue renin-angiotensin system induced by uric acid. Biochimie. 2019; 162: 125–133. PubMed: https://pubmed.ncbi.nlm.nih.gov/31002842/
  9. Vitseva OI, Tanriverdi K, Tchkonia TT, Kirkland JL, McDonnell ME, et al. Inducible Toll-like Receptor and NF-κB Regulatory Pathway Expression in Human Adipose Tissue. Obesity. 2008; 16: 932–937. PubMed: https://pubmed.ncbi.nlm.nih.gov/18292749/
  10. Poulain-Godefroy O, Froguel P. Preadipocyte response and impairment of differentiation in an inflammatory environment. Biochem Biophysi Res Commun. 2007; 356: 662–667.
  11. Yan Z-qun. Regulation of TLR4 Expression Is a Tale About Tail. Arterioscler Thromb Vasc Biol. 2006; 26: 2582–2584. PubMed: https://pubmed.ncbi.nlm.nih.gov/17110607/
  12. Bae J, Ricciardi CJ, Esposito D, Komarnytsky S, Hu P, et al. Activation of pattern recognition receptors in brown adipocytes induces inflammation and suppresses uncoupling protein 1 expression and mitochondrial respiration. Am J Physiol Cell Physiol. 2014; 306; C918-930. PubMed: https://pubmed.ncbi.nlm.nih.gov/24627558/
  13. Thomalla M, Schmid A, Neumann E, Pfefferle PI, Müller-Ladner U, et al. Evidence of an anti-inflammatory toll-like receptor 9 (TLR 9) pathway in adipocytes. J Endocrinol. 2019; 240: 325–343. PubMed: https://pubmed.ncbi.nlm.nih.gov/30508414/
  14. Zheng SL, Li ZY, Song J, Liu JM, Miao CY. Metrnl: a secreted protein with new emerging functions. Acta Pharmacologica Sinica. 2016; 37: 571–579. PubMed: https://pubmed.ncbi.nlm.nih.gov/27063217/
  15. Li ZY, Fan MB, Zhang SL, Qu Y, Zheng SL, et al. Intestinal Metrnl released into the gut lumen acts as a local regulator for gut antimicrobial peptides. Acta Pharmacologica Sinica. 2016; 37: 1458–1466.
  16. Ghosh SS, Wang J, Yannie PJ, Ghosh S. Intestinal Barrier Dysfunction, LPS Translocation, and Disease Development. J Endocr Soc. 2020; 4: bvz039. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033038/
  17. Bruun JM, Pedersen SB, Richelsen B. Regulation of Interleukin 8 Production and Gene Expression in Human Adipose Tissue in Vitro1. J Clin Endocrinol Metab. 2001; 86: 1267–1273. PubMed: https://pubmed.ncbi.nlm.nih.gov/11238519/
  18. Castro AM, Macedo-de la Concha LE, Pantoja-Meléndez CA. Low-grade inflammation and its relation to obesity and chronic degenerative diseases. Revista Médica del Hospital General de México. 2017; 80: 101–105.
  19. Kristóf E, Klusóczki Á, Veress R, Shaw A, Combi ZS, et al. Interleukin-6 released from differentiating human beige adipocytes improves browning. Exp Cell Res. 2019; 377: 47–55. PubMed: https://pubmed.ncbi.nlm.nih.gov/30794803/
  20. Hoareau L, Bencharif K, Rondeau P, Murumalla R, Ravanan P, et al. Signaling pathways involved in LPS induced TNFalpha production in human adipocytes. J Inflamm. 2010; 7: 1. PubMed: https://pubmed.ncbi.nlm.nih.gov/20148136/
  21. Severinsen MC, Pedersen BK. Muscle–Organ Crosstalk: The Emerging Roles of Myokines. Endocrine Rev. 2020; 41: 594–609. PubMed: https://pubmed.ncbi.nlm.nih.gov/32393961/
  22. Chaldakov GN, Fiore M, Stankulov IS, Hristova M, Antonelli A, et al. NGF, BDNF, leptin, and mast cells in human coronary atherosclerosis and metabolic syndrome. Arc Physiol Biochem. 2001; 109: 357-360. PubMed: https://pubmed.ncbi.nlm.nih.gov/11935372/
  23. Nakagomi A, Okada S, Yokoyama M, Yoshida Y, Shimizu I, et al. Role of the central nervous system and adipose tissue BDNF/TrkB axes in metabolic regulation. NPJ Aging Mech Dis. 2015; 1: 15009. PubMed: https://pubmed.ncbi.nlm.nih.gov/28721258/
  24. Marosi K, Mattson MP. BDNF mediates adaptive brain and body responses to energetic challenges. Trends Endocrinol Metab. 2014; 25: 89–98. PubMed: https://pubmed.ncbi.nlm.nih.gov/24361004/
  25. Villarroya F, Cereijo R, Villarroya J, Giralt M. Brown adipose tissue as a secretory organ. Nature Reviews Endocrinology. 2016; 13: 26–35. PubMed: https://pubmed.ncbi.nlm.nih.gov/27616452/

Figures:

Similar Articles

Recently Viewed

Read More

Most Viewed

Read More