Advertisement

Niclosamide piperazine prevents high-fat diet-induced obesity and diabetic symptoms in mice

  • Jingjing Guo
  • Hanlin Tao
  • Amer Alasadi
  • Qingrong Huang
  • Shengkan JinEmail author
Original Article

Abstract

Purpose

Obesity and type 2 diabetes (T2D) have become the major public health challenges globally. Mitochondrial uncoupling, which reduces intracellular lipid loads and corrects the underlying cause of insulin resistance, has emerged as a promising anti-obese and anti-diabetic intervention. Niclosamide is an anthelmintic drug approved by the US FDA with the mechanism of action that uncouples mitochondria of parasitic worms. Recently, niclosamide ethanolamine salt (NEN) was found to be a safe and effective hepatic mitochondrial uncoupler for the prevention and treatment of obesity and T2D in mouse models. The striking features of NEN prompt us to examine the anti-obese and anti-diabetic efficacy of other salt forms of niclosamide, with the ultimate goal to identify a suitable salt formulation for future clinical development. Here, we report the study with niclosamide piperazine salt (NPP), another salt form of niclosamide with documented safety profile.

Methods

Mitochondrial uncoupling activity of NEN and NPP were determined by oxygen consumption assay with Seahorse XF24e Analyzer, as well as by mitochondrial membrane potential measurement in cultured cells. The in vivo anti-diabetic and anti-obesity activities were determined in C57BL/6J mice fed high-fat diet (HFD) or HFD containing 2000 ppm. NPP for 11 weeks.

Results

Niclosamide piperazine salt showed a comparable mitochondrial uncoupling activity to NEN. Oral administration of NPP significantly reduced HFD-induced obesity, hyperglycemia and hepatic steatosis, and sensitized the insulin responses in mice.

Conclusions

Niclosamide piperazine salt may hold the promise to become an alternative to NEN as a drug lead for the treatment of obesity and T2D.

No level of evidence Animal study

Keywords

Diabetes Mitochondrial uncoupler Niclosamide Obesity 

Abbreviations

HFD

High-fat diet

NEN

Niclosamide ethanolamine salt

NPP

Niclosamide piperazine salt

T2D

Type 2 diabetes

TMRE

Tetramethylrhodamine ethyl ester

Notes

Compliance with ethical standards

Funding

This study was funded by Mito BioPharm.

Conflict of interest

S.J. is a founder of Mito BioPharm, which has licensed the patents surrounding the development of chemical mitochondrial uncouplers, including niclosamide ethanolamine and niclosamide piperazine (described here), for treating metabolic diseases.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

References

  1. 1.
    Chen L, Magliano DJ, Zimmet PZ (2012) The worldwide epidemiology of type 2 diabetes mellitus—present and future perspectives. Nat Rev Endocrinol 8:228–236. doi: 10.1038/nrendo.2011.183 CrossRefGoogle Scholar
  2. 2.
    Centers for Disease Control and Prevention (2017) National Diabetes Statistics Report: estimates of diabetes and its burden in the United States, 2017. US Department of Health and Human Services, Atlanta. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf
  3. 3.
    Ogden CL, Lamb MM, Carroll MD, Flegal KM (2010) Obesity and socioeconomic status in adults: United States, 2005–2008. NCHS Data Brief, 1–8. https://www.cdc.gov/nchs/data/databriefs/db50.pdf
  4. 4.
    Seidell JC (2000) Obesity, insulin resistance and diabetes—a worldwide epidemic. Br J Nutr 83(Suppl 1):S5–8. doi: 10.1017/S000711450000088X Google Scholar
  5. 5.
    Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B (2009) Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32:193–203. doi: 10.2337/dc08-9025 CrossRefGoogle Scholar
  6. 6.
    Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P, Clinical Guidelines Committee of the American College of Physicians (2012) Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med 156:218–231. doi: 10.7326/0003-4819-156-3-201202070-00011 CrossRefGoogle Scholar
  7. 7.
    Kahn BB, Flier JS (2010) Obesity and insulin resistance. J Clin Invest 106:473–481. doi: 10.1172/JCI10842 CrossRefGoogle Scholar
  8. 8.
    Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846. doi: 10.1038/nature05482 CrossRefGoogle Scholar
  9. 9.
    Muoio DM, Newgard CB (2006) Obesity-related derangements in metabolic regulation. Annu Rev Biochem 75:367–401. doi: 10.1146/annurev.biochem.75.103004.142512 CrossRefGoogle Scholar
  10. 10.
    Randle PJ (1998) Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 14:263–283. doi: 10.1002/(SICI)1099-0895(199812)14:4<263:AID-DMR233>3.0.CO;2-C CrossRefGoogle Scholar
  11. 11.
    Samuel VT, Petersen KF, Shulman GI (2010) Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375:2267–2277. doi: 10.1016/S0140-6736(10)60408-4 CrossRefGoogle Scholar
  12. 12.
    Perry RJ, Kim T, Zhang XM, Lee HY, Pesta D, Popov VB, Zhang D, Rahimi Y, Jurczak MJ, Cline GW, Spiegel DA, Shulman GI (2013) Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metab 18:740–748. doi: 10.1016/j.cmet.2013.10.004 CrossRefGoogle Scholar
  13. 13.
    Tao H, Zhang Y, Zeng X, Shulman GI, Jin S (2014) Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice. Nat Med 20:1263–1269. doi: 10.1038/nm.3699 CrossRefGoogle Scholar
  14. 14.
    Nedergaard J, Ricquier D, Kozak LP (2005) Uncoupling proteins: current status and therapeutic prospects. EMBO Rep 6:917–921. doi: 10.1038/sj.embor.7400532 CrossRefGoogle Scholar
  15. 15.
    Tseng YH, Cypess AM, Kahn CR (2010) Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov 9:465–482. doi: 10.1038/nrd3138 CrossRefGoogle Scholar
  16. 16.
    Kopecky J, Rossmeisl M, Flachs P, Bardova K, Brauner P (2001) Mitochondrial uncoupling and lipid metabolism in adipocytes. Biochem Soc Trans 29:791–797. doi: 10.1042/bst0290791 CrossRefGoogle Scholar
  17. 17.
    Harper ME, Green K, Brand MD (2008) The efficiency of cellular energy transduction and its implications for obesity. Annu Rev Nutr 28:13–33. doi: 10.1146/annurev.nutr.28.061807.155357 CrossRefGoogle Scholar
  18. 18.
    Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Investig 106:171–176. doi: 10.1172/JCI10583 CrossRefGoogle Scholar
  19. 19.
    Ishigaki Y, Katagiri H, Yamada T, Ogihara T, Imai J, Uno K, Hasegawa Y, Gao J, Ishihara H, Shimosegawa T, Sakoda H, Asano T, Oka Y (2005) Dissipating excess energy stored in the liver is a potential treatment strategy for diabetes associated with obesity. Diabetes 54:322–332. doi: 10.2337/diabetes.54.2.322 CrossRefGoogle Scholar
  20. 20.
    Anonymous (1998) Data sheet on pesticides no.63: niclosamide. World Health Organization: Food and Agriculture Organisation, International Programme on Chemical Safety, Inchem. Report no. WHO/VBC/DS/88.63Google Scholar
  21. 21.
    Al-Gareeb AI, Aljubory KD, Alkuraishy HM (2017) Niclosamide as an anti-obesity drug: an experimental study. Eat Weight Disord. doi: 10.1007/s40519-017-0373-1 Google Scholar
  22. 22.
    Hollingworth RM (2001) Inhibitors and uncouplers of mitochondrial oxidative phosphorylation. In: Krieger R (ed) Handbook of pesticide toxicology, 2nd edn. Academic Press, San Diego, pp 1169–1261CrossRefGoogle Scholar
  23. 23.
    Savjani KT, Gajjar AK, Savjani JK (2012) Drug solubility: importance and enhancement techniques. ISRN Pharm 2012:1–10. doi: 10.5402/2012/195727 Google Scholar
  24. 24.
    Andrews P, Thyssen J, Lorke D (1983) The biology and toxicology of molluscicides, bayluscide. Pharmacol Ther 19:245–295. doi: 10.1016/0163-7258(82)90064-X CrossRefGoogle Scholar
  25. 25.
    American Diabetes Association (2014) Standards of medical care in diabetes-2014. Diabetes Care 37(Suppl 1):S14–S80. doi: 10.2337/dc14-S014 CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Jingjing Guo
    • 1
  • Hanlin Tao
    • 2
  • Amer Alasadi
    • 3
  • Qingrong Huang
    • 1
  • Shengkan Jin
    • 2
    Email author
  1. 1.Department of Food ScienceRutgers UniversityNew BrunswickUSA
  2. 2.Department of PharmacologyRutgers University-Robert Wood Johnson Medical SchoolPiscatawayUSA
  3. 3.Department of PhysiologyRutgers University-Robert Wood Johnson Medical SchoolPiscatawayUSA

Personalised recommendations