Skip to main content

Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Inhibition of endoplasmic reticulum stress in high-fat-diet-induced obese C57BL/6 mice: Efficacy of a novel extract from mulberry (Morus alba) leaves fermented with Cordyceps militaris

  • 41 Accesses

  • 1 Citations

Abstract

A few clues about correlation between endoplasmic reticulum (ER) stress and mulberry (Morus alba) leaves were investigated in only the experimental autoimmune myocarditis and streptozotocin-induced diabetes. To investigate whether a novel extract of mulberry leaves fermented with Cordyceps militaris (EMfC) could suppress ER in fatty liver, alterations in the key parameters for ER stress response were measured in high fat diet (HFD)-induced obese C57L/6 mice treated with EMfC for 12 weeks. The area of adipocytes in the liver section were significantly decreased in the HFD+EMfC treated group as compared to the HFD+Vehicle treated group, while their level was higher in HFD+Vehicle treated group than No treated group. The level of the eukaryotic initiation factor 2 alpha (eIF2α) and inositol-requiring enzyme 1 beta (IRE1α) phosphorylation and CCAAT-enhancer-binding protein homologous protein (CHOP) expression were remarkably enhanced in the HFD+Vehicle treated group. However, their levels were restored in the HFD+EMfC treated group, although some differences were detected in the decrease rate. Similar recovery was observed on the ER stress-induced apoptosis. The level of Caspase-3, Bcl-2 and Bax were decreased in the HFD+EMfC and HFD+orlistat (OT) treated group compared to the HFD+Vehicle treated group. The results of the present study therefore provide first evidence that EMfC with the antiobesity effects can be suppressed ER stress and ER stress-induced apoptosis in the hepatic steatosis of HFD-induced obesity model.

References

  1. 1.

    Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8(7): 519–529.

  2. 2.

    Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, Patterson BW, Horton JD, Mittendorfer B, Hotamisligil GS, Klein S. Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes 2010; 59(8): 1899–1905.

  3. 3.

    Yoshida H. ER stress and diseases. FEBS J 2007; 274(3): 630–658.

  4. 4.

    Forman MS, Lee VM, Trojanowski JQ. ‘Unfolding’ pathways in neurodegenerative disease. Trends Neurosci 2003; 26(8): 407–410.

  5. 5.

    Ozcan L, Tabas I. Role of endoplasmic reticulum stress in metabolic disease and other disorders. Annu Rev Med 2012; 63: 317–328.

  6. 6.

    Kim JE, Go J, Sung JE, Lee HA, Seo EJ, Yun WB, Hwang DY. Laxative effects o. Liriope platyphylla are tightly correlated with suppression of endoplasmic reticulum stress in loperamideinduced constipation of SD rats. Lab Anim Res 2016; 32(1): 16–23.

  7. 7.

    Achard CS, Laybutt DR. Lipid-induced endoplasmic reticulum stress in liver cells results in two distinct outcomes: adaptation with enhanced insulin signaling or insulin resistance. Endocrinology 2012; 153(5): 2164–2177.

  8. 8.

    Jeong JW, Lee B, Kim DH, Jeong HO, Moon KM, Kim MJ, Yokozawa T, Chung HY. Mechanism of action of magnesium lithospermate B against aging and obesity-induces ER stress, insulin resistance, and inflammsome formation in the liver. Molecules 2018; 23(9): E2098.

  9. 9.

    Kim HM, Kim Y, Lee ES, Huh JH, Chung CH. Caffeic acid ameliorates hepatic steatosis and reduces ER stress in high fat diet-induced obese mice by regulating autophagy. Nutrition 2018; 55–56: 63–70.

  10. 10.

    Chen Y, Wu Z, Zhao S, Xiang R. Chemical chaperones reduce ER stress and adipose tissue inflammation in high fat diet-induced mouse model of obesity. Sci Rep 2016; 6: 27486.

  11. 11.

    Seoane-Collazo P, Martínez de Morentin PB, Fernø J, Diéguez C, Nogueiras R, López M. Nicotine improves obesity and hepatic steatosis and ER stress in diet-induced obese male rats. Endocrinology 2014;155(5):1679–1689.

  12. 12.

    Arumugam S, Thandavarayan RA, Veeraveedu PT, Ma M, Giridharan VV, Arozal W, Sari FR, Sukumaran V, Lakshmanan A, Soetikno V, Suzuki K, Kodama M, Watanabe K. Modulation of endoplasmic reticulum stress and cardiomyocyte apoptosis by mulberry leaf diet in experimental autoimmune myocarditis rats. J Clin Biochem Nutr 2012; 50(2): 139–144.

  13. 13.

    Arumugam S, Mito S, Thandavarayan RA, Giridharan VV, Pitchaimani V, Karuppagounder V, Harima M, Nomoto M, Suzuki K, Watanabe K. Mulberry leaf diet protects against progression of experimental autoimmune myocarditis to dilated cardiomyopathy via modulation of oxidative stress and MAPK-mediated apoptosis. Cardiovasc Ther 2013; 31(6): 352–362.

  14. 14.

    Lee MR, Kim JE, Yun WB, Choi JY, Park JJ, Kim HR, Song BR, Choi YW, Kim KM, Hwang DY. Lipolytic effect of novel extracts from mulberry (Morus alba) leaves fermented with Cordyceps militaris in the primary adipocytes derived from SD rats. Lab Anim Res 2017; 33(3): 270–279.

  15. 15.

    Scull CM, Tabas I. Mechanisms of ER stress-induced apoptosis in atherosclerosis. Arterioscler Thromb Vasc Biol 2011; 31(12): 2792–2797.

  16. 16.

    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306(5695): 457–461.

  17. 17.

    Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, Kellum JM, Sanyal AJ. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008; 134(2): 568–576.

  18. 18.

    Cnop M, Foufelle F, Velloso LA. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med 2012; 18(1): 59–68.

  19. 19.

    Oyadomari S, Harding HP, Zhang Y, Oyadomari M, Ron D. Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab 2008; 7(6): 520–532.

  20. 20.

    Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T, Ferré P, Foufelle F. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest 2009; 119(5): 1201–1215.

  21. 21.

    Heck AM, Yanovski JA, Calis KA. Orlistat, a new lipase inhibitor for the management of obesity. Pharmacotherapy 2000; 20(3): 270–279.

  22. 22.

    Zavoral JH. Treatment with orlistat reduces cardiovascular risk in obese patients. J Hypertens 1998; 16(12 Pt 2): 2013–2017.

  23. 23.

    Hollander PA, Elbein SC, Hirsch IB, Kelley D, McGill J, Taylor T, Weiss SR, Crockett SE, Kaplan RA, Comstock J, Lucas CP, Lodewick PA, Canovatchel W, Chung J, Hauptman J. Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care 1998; 21(8): 1288–1294.

  24. 24.

    Little JL, Wheeler FB, Fels DR, Koumenis C, Kridel SJ. Inhibition of fatty acid synthase induces endoplasmic reticulum stress in tumor cells. Cancer Res 2007; 67(3): 1262–1269.

Download references

Author information

Correspondence to Dae Youn Hwang.

Rights and permissions

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://doi.org/creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lee, M.R., Bae, S.J., Kim, J.E. et al. Inhibition of endoplasmic reticulum stress in high-fat-diet-induced obese C57BL/6 mice: Efficacy of a novel extract from mulberry (Morus alba) leaves fermented with Cordyceps militaris. Lab Anim Res 34, 288–294 (2018). https://doi.org/10.5625/lar.2018.34.4.288

Download citation

Keywords

  • Mulberry leaf
  • ER stress response
  • fatty liver
  • apoptosis