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Niclosamide piperazine prevents high-fat diet-induced obesity and diabetic symptoms in mice
Jingjing Guo1, Hanlin Tao2, Amer Alasadi3
1Department of Food Science, Rutgers University, New Brunswick, NJ, USA.
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.
Insights
Niclosamide piperazine salt (NPP) effectively reduces obesity and type 2 diabetes in mice by uncoupling mitochondria. This study suggests NPP as a potential alternative drug lead for metabolic disorders.
Area of Science:
- Biochemistry
- Pharmacology
- Metabolic Diseases
Background:
- Obesity and type 2 diabetes (T2D) are significant global health concerns.
- Mitochondrial uncoupling is a promising strategy to combat insulin resistance and reduce lipid accumulation.
- Niclosamide, an FDA-approved anthelmintic, exhibits mitochondrial uncoupling properties.
Purpose of the Study:
- To evaluate the anti-obesity and anti-diabetic potential of niclosamide piperazine salt (NPP).
- To compare the efficacy of NPP with niclosamide ethanolamine salt (NEN) as a mitochondrial uncoupler.
- To identify a suitable niclosamide salt formulation for future clinical development.
Main Methods:
- Mitochondrial uncoupling activity assessed via oxygen consumption and membrane potential assays.
- In vivo studies conducted on C57BL/6J mice fed a high-fat diet (HFD).
- Mice received HFD with or without NPP for 11 weeks to evaluate anti-diabetic and anti-obesity effects.
Main Results:
- Niclosamide piperazine salt demonstrated mitochondrial uncoupling activity comparable to NEN.
- Oral NPP administration significantly mitigated HFD-induced obesity, hyperglycemia, and hepatic steatosis.
- NPP treatment improved insulin sensitivity in mice.
Conclusions:
- Niclosamide piperazine salt shows promise as an alternative to NEN for treating obesity and T2D.
- NPP represents a potential drug lead for metabolic disease therapies.
- Further research is warranted, based on this animal study.
