Niclosamide piperazine prevents high-fat diet-induced obesity and diabetic symptoms in mice
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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.
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.
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.
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
KeywordsDiabetes Mitochondrial uncoupler Niclosamide Obesity
Niclosamide ethanolamine salt
Niclosamide piperazine salt
Type 2 diabetes
Tetramethylrhodamine ethyl ester
Compliance with ethical standards
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.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- 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.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
- 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.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
- 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
- 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
- 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.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