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

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Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity Aims and scope Submit manuscript

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

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Abbreviations

HFD:

High-fat diet

NEN:

Niclosamide ethanolamine salt

NPP:

Niclosamide piperazine salt

T2D:

Type 2 diabetes

TMRE:

Tetramethylrhodamine ethyl ester

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Authors and Affiliations

  1. Department of Food Science, Rutgers University, New Brunswick, NJ, USA

    Jingjing Guo & Qingrong Huang

  2. Department of Pharmacology, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA

    Hanlin Tao & Shengkan Jin

  3. Department of Physiology, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA

    Amer Alasadi

Authors
  1. Jingjing Guo
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  2. Hanlin Tao
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  3. Amer Alasadi
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  4. Qingrong Huang
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  5. Shengkan Jin
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Corresponding author

Correspondence to Shengkan Jin.

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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.

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Guo, J., Tao, H., Alasadi, A. et al. Niclosamide piperazine prevents high-fat diet-induced obesity and diabetic symptoms in mice. Eat Weight Disord 24, 91–96 (2019). https://doi.org/10.1007/s40519-017-0424-7

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  • DOI: https://doi.org/10.1007/s40519-017-0424-7

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