Niclosamide ethanolamine–induced mild mitochondrial uncoupling improves diabetic symptoms in mice

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Abstract

Type 2 diabetes (T2D) has reached an epidemic level globally. Most current treatments ameliorate the hyperglycemic symptom of the disease but are not effective in correcting its underlying cause. One important causal factor of T2D is ectopic accumulation of lipids in metabolically sensitive organs such as liver and muscle. Mitochondrial uncoupling, which reduces cellular energy efficiency and increases lipid oxidation, is an appealing therapeutic strategy. The challenge, however, is to discover safe mitochondrial uncouplers for practical use. Niclosamide is an anthelmintic drug approved by the US Food and Drug Administration that uncouples the mitochondria of parasitic worms. Here we show that niclosamide ethanolamine salt (NEN) uncouples mammalian mitochondria at upper nanomolar concentrations. Oral NEN increases energy expenditure and lipid metabolism in mice. It is also efficacious in preventing and treating hepatic steatosis and insulin resistance induced by a high-fat diet. Moreover, it improves glycemic control and delays disease progression in db/db mice. Given the well-documented safety profile of NEN, our study provides a potentially new and practical pharmacological approach for treating T2D.

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Figure 1: NEN uncouples mitochondrial respiration and affects mouse energy metabolism.
Figure 2: Oral NEN is effective in preventing and treating HFD-induced insulin resistance.
Figure 3: Oral NEN improves glycemic control in db/db mice.
Figure 4: Oral NEN is effective in preventing and reducing HFD-induced hepatic steatosis in mice.
Figure 5: Effect of NEN on cellular metabolism.

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Acknowledgements

We thank M. Kahn at the Yale University School of Medicine for the analysis of hepatocellular DAG and ceramide contents. We thank the US National Mouse Metabolic Phenotyping Centers (MMPC) at various sites for the various metabolic studies: C. Croniger and L. Wang at Case Western Reserve University (U24 DK076174) for the metabolic cage experiments; J. Kim and D.Y. Jung at the University of Massachusetts (U24 DK093000) for the hyperinsulinemic-euglycemic clamp studies and glycogen synthesis rate determination; and S.S. Wirth and J. Graham at University of California, Davis (U24 DK092993) for determination of glycated hemoglobin (HbA1c) in db/db mice. We also thank W. Hu and Y. Zhao at Rutgers University for assistance with the quantitative real-time PCR analyses and R. Patel at the Rutgers Core Facility for technical assistance with electron microscopy studies. H.T., Y.Z., X.Z. and S.J. are supported by the US National Institutes of Health (R01AG030081 and R01CA116088) and Mito Biopharm, LLC. G.I.S. is supported by the US National Institutes of Health (R24 DK085638, P30 DK45735 and U24 DK059635) and the Novo Nordisk Foundation for Basic Metabolic Research.

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H.T. and S.J. designed the experiments, analyzed the data and wrote the manuscript. H.T. conducted most of the experiments. Y.Z. conducted the mitochondrial oxygen consumption assay and contributed to the quantitative PCR analyses and other in vivo studies. X.Z. contributed to the discussion and design of some experiments. G.I.S. designed and supervised the analyses of hepatic lipid metabolites and contributed to revision of the manuscript. S.J. conceived and directed the project.

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Correspondence to Shengkan Jin.

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Competing interests

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

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Tao, H., Zhang, Y., Zeng, X. et al. Niclosamide ethanolamine–induced mild mitochondrial uncoupling improves diabetic symptoms in mice. Nat Med 20, 1263–1269 (2014). https://doi.org/10.1038/nm.3699

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