Type 2 diabetes (T2D) has reached an epidemic level globally. Most current treatments ameliorate the hyperglycemic symptom but are not effective in correcting the underlying cause. One important causal factor of T2D is ectopic accumulation of lipid in organs such as liver and muscle. Mitochondrial uncoupling, which reduces cellular energy efficiency and increases lipid oxidation, represents an appealing therapeutic strategy. The challenge, however, is to discover safe mitochondrial uncouplers for practical use. Niclosamide is an FDA approved anthelmintic drug that uncouples 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 efficacious in preventing and treating high-fat diet (HFD) induced hepatic steatosis and insulin resistance. Moreover, it improves glycemic control and delays disease progression of the db/db mice. Given the well- documented safety profile of NEN, our study provides a potentially practical pharmacological embodiment of a new strategy for treating T2D.

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