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Stachydrine alleviates lipid-induced skeletal muscle insulin resistance via AMPK/HO-1-mediated suppression of inflammation and endoplasmic reticulum stress

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Abstract

Objective

Insulin resistance develops due to skeletal muscle inflammation and endoplasmic reticulum (ER) stress. Stachydrine (STA), extracted from Leonurus heterophyllus, has been shown to suppress proliferation and induce apoptosis in breast cancer cells and exert anti-inflammatory properties in the brain, heart, and liver. However, the roles of STA in insulin signaling in skeletal muscle remain unclear. Herein, we examined the impacts of STA on insulin signaling in skeletal muscle under hyperlipidemic conditions and its related molecular mechanisms.

Methods

Various protein expression levels were determined by Western blotting. Levels of mouse serum cytokines were measured by ELISA.

Results

We found that STA-ameliorated inflammation and ER stress, leading to attenuation of insulin resistance in palmitate-treated C2C12 myocytes. STA dose-dependently enhanced AMPK phosphorylation and HO-1 expression. Administration of STA attenuated not only insulin resistance but also inflammation and ER stress in the skeletal muscle of high-fat diet (HFD)-fed mice. Additionally, STA-ameliorated glucose tolerance and insulin sensitivity, as well as serum TNFα and MCP-1, in mice fed a HFD. Small interfering (si) RNA-associated suppression of AMPK or HO-1 expression abolished the effects of STA in C2C12 myocytes.

Conclusions

These results suggest that STA activates AMPK/HO-1 signaling, resulting in reduced inflammation and ER stress, thereby improving skeletal muscle insulin resistance. Using STA as a natural ingredient, this research successfully treated insulin resistance and type 2 diabetes.

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Abbreviations

AMPK:

AMP-activated protein kinase

HO-1:

Heme oxygenase-1

ER stress:

Endoplasmic reticulum stress

References

  1. Saklayen MG (2018) The global epidemic of the metabolic syndrome. Curr Hypertens Rep 20(2):12

    Article  PubMed  PubMed Central  Google Scholar 

  2. Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14(2):88–98

    Article  PubMed  Google Scholar 

  3. Williams MD, Mitchell GM (2012) MicroRNAs in insulin resistance and obesity. Exp Diabetes Res 2012:484696

    Article  PubMed  PubMed Central  Google Scholar 

  4. Warram JH, Martin BC, Krolewski AS et al (1990) Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 113(12):909–915

    Article  CAS  PubMed  Google Scholar 

  5. Jove M, Planavila A, Laguna JC et al (2005) Palmitate-induced interleukin 6 production is mediated by protein kinase C and nuclear-factor kappaB activation and leads to glucose transporter 4 down-regulation in skeletal muscle cells. Endocrinology 146(7):3087–3095

    Article  CAS  PubMed  Google Scholar 

  6. Jornayvaz FR, Samuel VT, Shulman GI (2010) The role of muscle insulin resistance in the pathogenesis of atherogenic dyslipidemia and nonalcoholic fatty liver disease associated with the metabolic syndrome. Annu Rev Nutr 30:273–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Petersen KF, Dufour S, Savage DB et al (2007) The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A 104(31):12587–12594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang C, Shan XL, Liao YL et al (2014) Effects of stachydrine on norepinephrine-induced neonatal rat cardiac myocytes hypertrophy and intracellular calcium transients. BMC Complement Altern Med 14:474

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zhang J, Yang A, Wu Y et al (2018) Stachydrine ameliorates carbon tetrachloride-induced hepatic fibrosis by inhibiting inflammation, oxidative stress and regulating MMPs/TIMPs system in rats. Biomed Pharmacother 97:1586–1594

    Article  CAS  PubMed  Google Scholar 

  10. Zhao L, Wu D, Sang M et al (2017) Stachydrine ameliorates isoproterenol-induced cardiac hypertrophy and fibrosis by suppressing inflammation and oxidative stress through inhibiting NF-kappaB and JAK/STAT signaling pathways in rats. Int Immunopharmacol 48:102–109

    Article  CAS  PubMed  Google Scholar 

  11. Yu N, Hu S, Hao Z (2018) Benificial effect of stachydrine on the traumatic brain injury induced neurodegeneration by attenuating the expressions of Akt/mTOR/PI3K and TLR4/NFkappa-B pathway. Transl Neurosci 9:175–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kim TJ, Lee HJ, Pyun DH et al (2021) Valdecoxib improves lipid-induced skeletal muscle insulin resistance via simultaneous suppression of inflammation and endoplasmic reticulum stress. Biochem Pharmacol 188:114557

    Article  CAS  PubMed  Google Scholar 

  13. Liu X, Shan X, Chen H et al (2019) Stachydrine ameliorates cardiac fibrosis through inhibition of angiotensin II/transformation growth factor beta1 fibrogenic axis. Front Pharmacol 10:538

    Article  PubMed  PubMed Central  Google Scholar 

  14. Olivares-Reyes JA, Arellano-Plancarte A, Castillo-Hernandez JR (2009) Angiotensin II and the development of insulin resistance: implications for diabetes. Mol Cell Endocrinol 302(2):128–139

    Article  CAS  PubMed  Google Scholar 

  15. Jung TW, Kim HC, Kim HU et al (2019) Asprosin attenuates insulin signaling pathway through PKCdelta-activated ER stress and inflammation in skeletal muscle. J Cell Physiol 234(11):20888–20899

    Article  CAS  PubMed  Google Scholar 

  16. Jung TW, Lee SH, Kim HC et al (2018) METRNL attenuates lipid-induced inflammation and insulin resistance via AMPK or PPARdelta-dependent pathways in skeletal muscle of mice. Exp Mol Med 50(9):1–11

    Article  PubMed  Google Scholar 

  17. Lee W, Yun S, Choi GH et al (2018) BAIBA attenuates the expression of inflammatory cytokines and attachment molecules and ER stress in HUVECs and THP-1 cells. Pathobiology 85(5–6):280–288

    Article  PubMed  Google Scholar 

  18. Lee W, Yun S, Choi GH et al (2018) Fibronectin Type III Domain Containing 4 attenuates hyperlipidemia-induced insulin resistance via suppression of inflammation and ER stress through HO-1 expression in adipocytes. Biochem Biophys Res Commun 502(1):129–136

    Article  CAS  PubMed  Google Scholar 

  19. Kwon CH, Sun JL, Kim MJ et al (2020) Clinically confirmed DEL-1 as a myokine attenuates lipid-induced inflammation and insulin resistance in 3T3-L1 adipocytes via AMPK/HO-1- pathway. Adipocyte 9(1):576–586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sun JL, Abd El-Aty AM, Jeong JH et al (2020) Ginsenoside Rb2 ameliorates LPS-induced inflammation and ER stress in HUVECs and THP-1 cells via the AMPK-mediated pathway. Am J Chin Med 48(4):967–985

    Article  CAS  PubMed  Google Scholar 

  21. Koves TR, Ussher JR, Noland RC et al (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7(1):45–56

    Article  CAS  PubMed  Google Scholar 

  22. Foretz M, Even PC, Viollet B (2018) AMPK activation reduces hepatic lipid content by increasing fat oxidation in vivo. Int J Mol Sci. https://doi.org/10.3390/ijms19092826

    Article  PubMed  PubMed Central  Google Scholar 

  23. Thomson DM, Winder WW (2009) AMP-activated protein kinase control of fat metabolism in skeletal muscle. Acta Physiol (Oxf) 196(1):147–154

    Article  CAS  Google Scholar 

  24. Daval M, Foufelle F, Ferre P (2006) Functions of AMP-activated protein kinase in adipose tissue. J Physiol 574(Pt 1):55–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kim B, Kim MS, Hyun CK (2017) Syringin attenuates insulin resistance via adiponectin-mediated suppression of low-grade chronic inflammation and ER stress in high-fat diet-fed mice. Biochem Biophys Res Commun 488(1):40–45

    Article  CAS  PubMed  Google Scholar 

  26. Boden G (1997) Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46(1):3–10

    Article  CAS  PubMed  Google Scholar 

  27. Coll T, Eyre E, Rodriguez-Calvo R et al (2008) Oleate reverses palmitate-induced insulin resistance and inflammation in skeletal muscle cells. J Biol Chem 283(17):11107–11116

    Article  CAS  PubMed  Google Scholar 

  28. Senn JJ (2006) Toll-like receptor-2 is essential for the development of palmitate-induced insulin resistance in myotubes. J Biol Chem 281(37):26865–26875

    Article  CAS  PubMed  Google Scholar 

  29. Shi H, Kokoeva MV, Inouye K et al (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116(11):3015–3025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kim JK, Kim YJ, Fillmore JJ et al (2001) Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 108(3):437–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hu Y, Mao A, Yu Z et al (2016) Anti-endotoxin and anti-inflammatory effects of Chinese herbal medicinal alkaloid ingredients in vivo. Microb Pathog 99:51–55

    Article  CAS  PubMed  Google Scholar 

  32. Yilmaz E (2017) Endoplasmic reticulum stress and obesity. Adv Exp Med Biol 960:261–276

    Article  CAS  PubMed  Google Scholar 

  33. Li M, Zhang Y, Cao Y et al (2018) Icariin ameliorates palmitate-induced insulin resistance through reducing thioredoxin-interacting protein (TXNIP) and suppressing ER stress in C2C12 myotubes. Front Pharmacol 9:1180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hardie DG, Schaffer BE, Brunet A (2016) AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol 26(3):190–201

    Article  CAS  PubMed  Google Scholar 

  35. Woods A, Williams JR, Muckett PJ et al (2017) Liver-specific activation of AMPK prevents steatosis on a high-fructose diet. Cell Rep 18(13):3043–3051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Musi N, Goodyear LJ (2003) AMP-activated protein kinase and muscle glucose uptake. Acta Physiol Scand 178(4):337–345

    Article  CAS  PubMed  Google Scholar 

  37. Maines MD (1997) The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 37:517–554

    Article  CAS  PubMed  Google Scholar 

  38. Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A 61(2):748–755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Trakshel GM, Kutty RK, Maines MD (1986) Purification and characterization of the major constitutive form of testicular heme oxygenase. The noninducible isoform. J Biol Chem 261(24):11131–11137

    Article  CAS  PubMed  Google Scholar 

  40. Xin G, Du J, Wang YT et al (2014) Effect of oxidative stress on heme oxygenase-1 expression in patients with gestational diabetes mellitus. Exp Ther Med 7(2):478–482

    Article  CAS  PubMed  Google Scholar 

  41. Takahashi T, Shimizu H, Morimatsu H et al (2007) Heme oxygenase-1: a fundamental guardian against oxidative tissue injuries in acute inflammation. Mini Rev Med Chem 7(7):745–753

    Article  CAS  PubMed  Google Scholar 

  42. Liu XM, Peyton KJ, Ensenat D et al (2005) Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in vascular smooth muscle. Role in cell survival. J Biol Chem 280(2):872–877

    Article  CAS  PubMed  Google Scholar 

  43. Le WD, Xie WJ, Appel SH (1999) Protective role of heme oxygenase-1 in oxidative stress-induced neuronal injury. J Neurosci Res 56(6):652–658

    Article  CAS  PubMed  Google Scholar 

  44. Jung TW, Kim HC, Abd El-Aty AM et al (2017) Protectin DX suppresses hepatic gluconeogenesis through AMPK-HO-1-mediated inhibition of ER stress. Cell Signal 34:133–140

    Article  CAS  PubMed  Google Scholar 

  45. Minnich A, Tian N, Byan L et al (2001) A potent PPARalpha agonist stimulates mitochondrial fatty acid beta-oxidation in liver and skeletal muscle. Am J Physiol Endocrinol Metab 280(2):E270-279

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. NRF-2021R1F1A1050004 and No. 2022R1A2B5B01001453).

Author information

Author notes

  1. T. W. Jung and H. Kim contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea

    T. W. Jung, H. Kim, S. Y. Park, W. Cho, H. Oh & J. H. Jeong

  2. Department of Anatomy and Cell Biology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea

    H. J. Lee

  3. Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea

    S. Y. Park, H. J. Lee & J. H. Jeong

  4. Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt

    A. M. Abd El-Aty

  5. Department of Medical Pharmacology, Medical Faculty, Ataturk University, 25240, Erzurum, Türkiye

    A. M. Abd El-Aty & A. Hacimuftuoglu

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  1. T. W. Jung
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Correspondence to J. H. Jeong.

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Ethical approval

Animal experiments were approved by the Institutional Animal Care and Use Committee of Chung-Ang University, Seoul, Republic of Korea (Approval No.: 2020-00048) and carried out according to the Guide for the Care and Use of Laboratory Animals (NIH publication, 8th edition, 2011).

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Supplementary Information

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40618_2022_1866_MOESM1_ESM.tif

Supplementary file1. Figure S1. STA does not affect palmitate-induced TG accumulation and does not modulate insulin-stimulated ERK1/2 signaling. A Western blotting of phosphorylated ERK1/2 expression in C2C12 myocytes treated with palmitate (200 μM) and/or STA (20 μM) for 24 h. Human insulin (5 nM) was used to upregulate insulin signaling for 3 min. B Oil red O-based TG measurement in C2C12 myocytes in the presence of palmitate (200 μM) and/or STA (0-20 μM) for 24 h. Means ± SEM were calculated from three independent experiments. Significance (P < 0.05) *: vs insulin-treated control or control. (TIF 117 KB)

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Jung, T.W., Kim, H., Park, S.Y. et al. Stachydrine alleviates lipid-induced skeletal muscle insulin resistance via AMPK/HO-1-mediated suppression of inflammation and endoplasmic reticulum stress. J Endocrinol Invest 45, 2181–2191 (2022). https://doi.org/10.1007/s40618-022-01866-8

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  • DOI: https://doi.org/10.1007/s40618-022-01866-8

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