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Deletion of SIRT1 in myeloid cells impairs glucose metabolism with enhancing inflammatory response to adipose tissue hypoxia

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Abstract

Chronic inflammation is a pathophysiology of insulin resistance in metabolic diseases, such as obesity and type 2 diabetes. Adipose tissue macrophages (ATMs) play important roles in this inflammatory process. SIRT1 is implicated in the regulation of glucose metabolism in some metabolic tissues, such as liver or skeletal muscle. This study was performed to investigate whether SIRT1 in macrophages played any roles in the regulation of inflammation and glucose metabolism. Myeloid cell-specific SIRT1-knockout mice were originally generated and analyzed under chow-fed and high-fat-fed conditions. Myeloid cell-specific SIRT1 deletion impaired insulin sensitivity and glucose tolerance assessed by the glucose- or insulin-tolerance test, which was associated with the enhanced expression of inflammation-related genes in epididymal adipose tissue of high-fat-fed mice. Interestingly, the M1 ATMs from the SIRT1-knockout mice showed more hypoxic and inflammatory phenotypes than those from control mice. The expressions of some inflammatory genes, such as Il1b and Nos2, which were induced by in vitro hypoxia treatment, were further enhanced by SIRT1 deletion along with the increased acetylation of HIF-1α in cultured macrophages. These results suggest that deletion of SIRT1 in myeloid cells impairs glucose metabolism by enhancing the hypoxia and inflammatory responses in ATMs, thereby possibly representing a novel therapeutic target for metabolic diseases, such as type 2 diabetes.

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References

  1. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415–45.

    Article  CAS  PubMed  Google Scholar 

  2. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132(6):2169–80.

    Article  CAS  PubMed  Google Scholar 

  3. Winer S, et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med. 2009;15(8):921–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Elgazar-Carmon V, et al. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res. 2008;49(9):1894–903.

    Article  CAS  PubMed  Google Scholar 

  5. Weisberg SP, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest. 2006;116(1):115–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Weisberg SP, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Xu H, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.

    Article  CAS  PubMed  Google Scholar 

  9. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117(1):175–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fujisaka S, et al. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes. 2009;58(11):2574–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lumeng CN, et al. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes. 2008;57(12):3239–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shaul ME, et al. Dynamic, M2-like remodeling phenotypes of CD11c + adipose tissue macrophages during high-fat diet–induced obesity in mice. Diabetes. 2010;59(5):1171–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hosogai N, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes. 2007;56(4):901–11.

    Article  CAS  PubMed  Google Scholar 

  15. Rausch ME, et al. Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond). 2008;32(3):451–63.

    Article  CAS  Google Scholar 

  16. Ye J, et al. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab. 2007;293(4):E1118–28.

    Article  CAS  PubMed  Google Scholar 

  17. Halberg N, et al. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol. 2009;29(16):4467–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cummins EP, et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci USA. 2006;103(48):18154–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rius J, et al. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature. 2008;453(7196):807–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tannahill GM, et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013;496(7444):238–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ye J. Adipose tissue vascularization: its role in chronic inflammation. Curr Diab Rep. 2011;11(3):203–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fujisaka S, et al. Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1alpha-dependent and HIF-1alpha-independent manner in obese mice. Diabetologia. 2013;56(6):1403–12.

    Article  CAS  PubMed  Google Scholar 

  23. Imai S, et al. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403(6771):795–800.

    Article  CAS  PubMed  Google Scholar 

  24. Luo J, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001;107(2):137–48.

    Article  CAS  PubMed  Google Scholar 

  25. Yeung F, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004;23(12):2369–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rodgers JT, et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434(7029):113–8.

    Article  CAS  PubMed  Google Scholar 

  27. Lim JH, et al. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell. 2010;38(6):864–78.

    Article  CAS  PubMed  Google Scholar 

  28. Baur JA, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444(7117):337–42.

    Article  CAS  PubMed  Google Scholar 

  29. Gerhart-Hines Z, et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J. 2007;26(7):1913–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhong L, Mostoslavsky R. Fine tuning our cellular factories: sirtuins in mitochondrial biology. Cell Metab. 2011;13(6):621–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Purushotham A, et al. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 2009;9(4):327–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang RH, et al. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest. 2011;121(11):4477–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schenk S, et al. Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. J Clin Invest. 2011;121(11):4281–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pfluger PT, et al. Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci USA. 2008;105(28):9793–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Schug TT, et al. Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol Cell Biol. 2010;30(19):4712–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lagouge M, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006;127(6):1109–22.

    Article  CAS  PubMed  Google Scholar 

  37. Milne JC, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007;450(7170):712–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Feige JN, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 2008;8(5):347–58.

    Article  CAS  PubMed  Google Scholar 

  39. Yamazaki Y, et al. Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice. Am J Physiol Endocrinol Metab. 2009;297(5):E1179–86.

    Article  CAS  PubMed  Google Scholar 

  40. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40(2):294–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dioum EM, et al. Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science. 2009;324(5932):1289–93.

    Article  CAS  PubMed  Google Scholar 

  42. Zhong L, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell. 2010;140(2):280–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Miya K, et al. Serine racemase is predominantly localized in neurons in mouse brain. J Comp Neurol. 2008;510(6):641–54.

    Article  CAS  PubMed  Google Scholar 

  44. Kanki H, Suzuki H, Itohara S. High-efficiency CAG-FLPe deleter mice in C57BL/6J background. Exp Anim. 2006;55(2):137–41.

    Article  CAS  PubMed  Google Scholar 

  45. Clausen BE, et al. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 1999;8(4):265–77.

    Article  CAS  PubMed  Google Scholar 

  46. Keith B, Johnson RS, Simon MC. HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2012;12(1):9–22.

    CAS  Google Scholar 

  47. Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA. 1993;90(9):4304–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, Japan (18209033 and 21591126 to K.T., 21790867 to Y.K., 22590971 and 50377272 to I.U. and 30512082 to S.F.). We thank Ms. Kana Sugihara and Dr. Qun Zhang for their excellent technical assistance. We also thank Dr. Hikari Suzuki and Dr. Yu Kato for their useful discussions.

Conflict of interest

The authors have no conflict of interest related to the current study.

Ethical standard

All institutional and national guidelines for the care and use of laboratory animals were followed.

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Authors and Affiliations

  1. First Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Akiko Takikawa, Isao Usui, Shiho Fujisaka, Satoko Senda, Yukiko Koshimizu & Kazuyuki Tobe

  2. Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan

    Masashi Ikutani & Yoshinori Nagai

  3. Department of Clinical Pharmacology, University of Toyama, Toyama, Japan

    Shinpei Hattori & Toshiyasu Sasaoka

  4. Department of Diagnostic Pathology, University of Toyama, Toyama, Japan

    Koichi Tsuneyama

  5. Department of Molecular Neuroscience, University of Toyama, Toyama, Japan

    Ran Inoue, Ayumi Tanaka-Hayashi & Hisashi Mori

  6. Frontier Research Core for Life Science, University of Toyama, Toyama, Japan

    Takashi Nakagawa

  7. Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan

    Kiyoshi Takatsu

Authors
  1. Akiko Takikawa
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Correspondence to Isao Usui or Kazuyuki Tobe.

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Takikawa, A., Usui, I., Fujisaka, S. et al. Deletion of SIRT1 in myeloid cells impairs glucose metabolism with enhancing inflammatory response to adipose tissue hypoxia. Diabetol Int 7, 59–68 (2016). https://doi.org/10.1007/s13340-015-0213-3

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  • DOI: https://doi.org/10.1007/s13340-015-0213-3

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