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Myricetin-induced brown adipose tissue activation prevents obesity and insulin resistance in db/db mice

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Abstract

Purpose

Myricetin, a dietary flavonoid, is effective in the treatment of obesity and insulin resistance by increasing glucose transport and lipogenesis in adipocyte and diminishing systemic inflammation in obesity. However, it has not been revealed yet whether myricetin is associated with brown adipose tissue (BAT) activation that tightly mediates systemic energy metabolism. Therefore, this study assessed whether myricetin activated brown adipose tissue in db/db mouse.

Methods

Myricetin (400 mg/kg) in distilled water was fed daily by oral gavage to leptin receptor-deficient db/db male mice at 4 weeks of age for 14 weeks. Body weight change, glucose intolerance test, blood lipid profile and BAT activation using PET-CT were assessed.

Results

After myricetin treatment for 14 weeks, systemic insulin resistance and hepatic steatosis were significantly improved in db/db mice with body weight reduction and myricetin led to decreased adipocity, improved plasma lipid profiles and increased energy expenditure. Myricetin activated BAT by upregulating thermogenic protein expression and activating mitochondrial biogenesis, eventually increasing heat dissipation in skin after cold exposure. In iWAT, myricetin induced beige formation, increased thermogenic protein expression and activated mitochondrial biogenesis. Consistently, thermogenic gene expression was upregulated when myricetin was introduced in C3H10T1/2 cells during brown adipocytes differentiation. Moreover, the expression level of adiponectin was significantly increased in C3H10T1/2 cells, adipose tissues and plasma after myricetin treatment.

Conclusions

These results highlight that myricetin prevents obesity and systemic insulin resistance by activating BAT and increasing adiponectin expression in BAT.

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Abbreviations

BAT:

Brown adipose tissue

iWAT:

Inguinal white adipose tissue

PGC1-α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PGC1-β:

Peroxisome proliferator-activated receptor gamma coactivator 1-beta

UCP1:

Uncoupling protein-1

CHO:

Cholesterol

TG:

Triacylglyceride

LDL:

Low-density lipoprotein

HDL:

High-density lipoprotein

ATP5A:

ATP synthase, H + transporting, mitochondrial F1 complex, alpha 1

UQCRC2:

Cytochrome b-c1 complex subunit 2

SDHB:

Succinate dehydrogenase [ubiquinone] iron–sulfur subunit, mitochondrial

SIRT1:

NAD-dependent deacetylase sirtuin-1

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

TH:

Tyrosine hydroxylase

dio2:

Dopamine and iodothyronine deiodinase types 2

TBX1:

T-box transcription factor TBX1

TMEM26:

Transmembrane protein 26

References

  1. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF, Loria CM, Millen BE, Nonas CA, Pi-Sunyer FX, Stevens J, Stevens VJ, Wadden TA, Wolfe BM, Yanovski SZ (2014) 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 63 (25 Pt B):2985–3023. doi:10.1016/j.jacc.2013.11.004

    Article  Google Scholar 

  2. Flegal KM, Kit BK, Orpana H, Graubard BI (2013) Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. Jama 309(1):71–82. doi:10.1001/jama.2012.113905

    Article  CAS  Google Scholar 

  3. Solas M, Milagro FI, Martinez-Urbistondo D, Ramirez MJ, Martinez JA (2016) Precision obesity treatments including pharmacogenetic and nutrigenetic approaches. Trends Pharmacol Sci 37(7):575–593. doi:10.1016/j.tips.2016.04.008

    Article  CAS  Google Scholar 

  4. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerback S, Nuutila P (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360(15):1518–1525. doi:10.1056/NEJMoa0808949

    Article  CAS  Google Scholar 

  5. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360(15):1500–1508. doi:10.1056/NEJMoa0808718

    Article  Google Scholar 

  6. Sidossis L, Kajimura S (2015) Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest 125(2):478–486. doi:10.1172/JCI78362

    Article  Google Scholar 

  7. Schulz TJ, Tseng YH (2009) Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Cytokine Growth Factor Rev 20(5–6):523–531. doi:10.1016/j.cytogfr.2009.10.019

    Article  CAS  Google Scholar 

  8. Gesta S, Tseng YH, Kahn CR (2007) Developmental origin of fat: tracking obesity to its source. Cell 131(2):242–256. doi:10.1016/j.cell.2007.10.004

    Article  CAS  Google Scholar 

  9. Kim SH, Plutzky J (2016) Brown fat and browning for the treatment of obesity and related metabolic disorders. Diabetes Metab J 40(1):12–21. doi:10.4093/dmj.2016.40.1.12

    Article  Google Scholar 

  10. Hankir MK, Cowley MA, Fenske WK (2016) A BAT-centric approach to the treatment of diabetes: turn on the brain. Cell Metab 24(1):31–40. doi:10.1016/j.cmet.2016.05.003

    Article  CAS  Google Scholar 

  11. Liu X, Zheng Z, Zhu X, Meng M, Li L, Shen Y, Chi Q, Wang D, Zhang Z, Li C, Li Y, Xue Y, Speakman JR, Jin W (2013) Brown adipose tissue transplantation improves whole-body energy metabolism. Cell Res 23(6):851–854. doi:10.1038/cr.2013.64

    Article  CAS  Google Scholar 

  12. Liu X, Wang S, You Y, Meng M, Zheng Z, Dong M, Lin J, Zhao Q, Zhang C, Yuan X, Hu T, Liu L, Huang Y, Zhang L, Wang D, Zhan J, Jong Lee H, Speakman JR, Jin W (2015) Brown adipose tissue transplantation reverses obesity in Ob/Ob Mice. Endocrinology 156(7):2461–2469. doi:10.1210/en.2014-1598

    Article  CAS  Google Scholar 

  13. Yuan X, Hu T, Zhao H, Huang Y, Ye R, Lin J, Zhang C, Zhang H, Wei G, Zhou H, Dong M, Zhao J, Wang H, Liu Q, Lee HJ, Jin W, Chen ZJ (2016) Brown adipose tissue transplantation ameliorates polycystic ovary syndrome. Proc Natl Acad Sci USA. doi:10.1073/pnas.1523236113

    Google Scholar 

  14. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng Y, Doria A, Kolodny GM, Kahn CR (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360(15):1509–1517

    Article  CAS  Google Scholar 

  15. Ohno H, Shinoda K, Spiegelman BM, Kajimura S (2012) PPARgamma agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab 15(3):395–404. doi:10.1016/j.cmet.2012.01.019

    Article  CAS  Google Scholar 

  16. Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV, Cannon B, Nedergaard J (2013) UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep 5(5):1196–1203. doi:10.1016/j.celrep.2013.10.044

    Article  CAS  Google Scholar 

  17. Min SY, Kady J, Nam M, Rojas-Rodriguez R, Berkenwald A, Kim JH, Noh HL, Kim JK, Cooper MP, Fitzgibbons T, Brehm MA, Corvera S (2016) Human ‘brite/beige’ adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat Med 22(3):312–318. doi:10.1038/nm.4031

    Article  CAS  Google Scholar 

  18. Miean KH, Mohamed S (2001) Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. J Agric Food Chem 49(6):3106–3112

    Article  CAS  Google Scholar 

  19. Semwal DK, Semwal RB, Combrinck S, Viljoen A (2016) Myricetin: a dietary molecule with diverse biological activities. Nutrients 8(2):90. doi:10.3390/nu8020090

    Article  Google Scholar 

  20. Ong KC, Khoo HE (2000) Effects of myricetin on glycemia and glycogen metabolism in diabetic rats. Life Sci 67(14):1695–1705

    Article  CAS  Google Scholar 

  21. Kandasamy N, Ashokkumar N (2014) Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin-cadmium induced diabetic nephrotoxic rats. Toxicol Appl Pharmacol 279(2):173–185. doi:10.1016/j.taap.2014.05.014

    Article  CAS  Google Scholar 

  22. Choi HN, Kang MJ, Lee SJ, Kim JI (2014) Ameliorative effect of myricetin on insulin resistance in mice fed a high-fat, high-sucrose diet. Nutr Res Pract 8 (5):544–549. doi:10.4162/nrp.2014.8.5.544

    Article  Google Scholar 

  23. Guo J, Meng Y, Zhao Y, Hu Y, Ren D, Yang X (2015) Myricetin derived from Hovenia dulcis Thunb. ameliorates vascular endothelial dysfunction and liver injury in high choline-fed mice. Food Funct 6 (5):1620–1634. doi:10.1039/c4fo01073f

    Article  CAS  Google Scholar 

  24. Chi QS, Wang DH (2011) Thermal physiology and energetics in male desert hamsters (Phodopus roborovskii) during cold acclimation. J Comp Physiol B 181(1):91–103. doi:10.1007/s00360-010-0506-6

    Article  Google Scholar 

  25. Chen HC, Farese RV Jr (2002) Determination of adipocyte size by computer image analysis. J Lipid Res 43(6):986–989

    CAS  Google Scholar 

  26. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408. doi:10.1006/meth.2001.1262

    Article  CAS  Google Scholar 

  27. Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, Tavernier G, Langin D, Spiegelman BM (2007) Transcriptional control of brown fat determination by PRDM16. Cell Metab 6(1):38–54. doi:10.1016/j.cmet.2007.06.001

    Article  CAS  Google Scholar 

  28. Wang B, Chandrasekera PC, Pippin JJ (2014) Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes. Curr Diabetes Rev 10(2):131–145

    Article  CAS  Google Scholar 

  29. de Luca C, Kowalski TJ, Zhang Y, Elmquist JK, Lee C, Kilimann MW, Ludwig T, Liu SM, Chua SC Jr (2005) Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J Clin Invest 115(12):3484–3493. doi:10.1172/jci24059

    Article  Google Scholar 

  30. Rosen ED, Spiegelman BM (2014) What we talk about when we talk about fat. Cell 156(1–2):20–44. doi:10.1016/j.cell.2013.12.012

    Article  CAS  Google Scholar 

  31. Himms-Hagen J (1984) Nonshivering thermogenesis. Brain Res Bull 12(2):151–160

    Article  CAS  Google Scholar 

  32. Ribeiro MO, Carvalho SD, Schultz JJ, Chiellini G, Scanlan TS, Bianco AC, Brent GA (2001) Thyroid hormone–sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform–specific. J Clin Invest 108(1):97–105. doi:10.1172/jci12584

    Article  CAS  Google Scholar 

  33. Cohen P, Spiegelman BM (2015) Brown and beige fat: molecular parts of a thermogenic machine. Diabetes 64(7):2346–2351. doi:10.2337/db15-0318

    Article  CAS  Google Scholar 

  34. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, Spiegelman BM (2012) Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150(2):366–376. doi:10.1016/j.cell.2012.05.016

    Article  CAS  Google Scholar 

  35. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7(8):941–946. doi:10.1038/90984

    Article  CAS  Google Scholar 

  36. Carey AL, Kingwell BA (2013) Brown adipose tissue in humans: therapeutic potential to combat obesity. Pharmacol Ther 140(1):26–33. doi:10.1016/j.pharmthera.2013.05.009

    Article  CAS  Google Scholar 

  37. Bi S, Li L (2013) Browning of white adipose tissue: role of hypothalamic signaling. Ann N Y Acad Sci 1302:30–34. doi:10.1111/nyas.12258

    Article  CAS  Google Scholar 

  38. Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS, Hubbard BP, Varela AT, Davis JG, Varamini B, Hafner A, Moaddel R, Rolo AP, Coppari R, Palmeira CM, de Cabo R, Baur JA, Sinclair DA (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15(5):675–690. doi:10.1016/j.cmet.2012.04.003

    Article  CAS  Google Scholar 

  39. Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813(7):1269–1278. doi:10.1016/j.bbamcr.2010.09.019

    Article  CAS  Google Scholar 

  40. Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmuller A, Gordts PL, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, Heeren J (2011) Brown adipose tissue activity controls triglyceride clearance. Nat Med 17(2):200–205. doi:10.1038/nm.2297

    Article  CAS  Google Scholar 

  41. Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T, Saito M (2013) Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 123(8):3404–3408. doi:10.1172/jci67803

    Article  CAS  Google Scholar 

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Acknowledgements

The authors declare that they have no conflict of interest. W.J., H.J.L. and H.L. designed the experiments. T.H., X.Y. and G.W performed the experiments and analyzed the data. W.J., H.J.L. and H.L. interpreted the data and wrote or revised the manuscript. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. This work was supported by the Strategic Priority Research Program (XDB13030000), National Program on Key Basic Research Project (973 Program), the Ministry of Science and Technology of China (2015CB943102, 2012CBA01301 and 2012CB944701, respectively) and the National Natural Science Foundation of China (81370951 and 81600658).

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Author notes

  1. Hyuek Jong Lee

    Present address: Center for Vascular Research, Institute for Basic Science (IBS), Daejeon, 34141, Republic of Korea

Authors and Affiliations

  1. Department of Anatomy, Basic Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China

    Tao Hu

  2. Key laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People’s Republic of China

    Tao Hu, Xiaoxue Yuan, Gang Wei, Hyuek Jong Lee & Wanzhu Jin

  3. State key Laboratory of Agrobiotechnology, Department of Animal Physiology, College of Biological Sciences, China Agricultural University, Beijing, 100193, People’s Republic of China

    Haoshu Luo

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Correspondence to Haoshu Luo, Hyuek Jong Lee or Wanzhu Jin.

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Hu, T., Yuan, X., Wei, G. et al. Myricetin-induced brown adipose tissue activation prevents obesity and insulin resistance in db/db mice. Eur J Nutr 57, 391–403 (2018). https://doi.org/10.1007/s00394-017-1433-z

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