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Application of Safe Mitochondrial Uncoupler for Treating Metabolic Diseases

by
Hanlin Tao
M.S., Nankai University - 2003


Thesis Advisor: Shengkan Jin, Ph.D.
Graduate Program in Cellular & Molecular Pharmacology


Pharmacology Department Conference Room
4th floor, RWJMS Research Tower
Piscataway

Friday, March 7, 2014
10:00 a.m.


Abstract

Mitochondrial respiration uncoupling is a process that dissipates the proton gradient independent of ATP synthase resulting in dissociation of the link between substrate oxidation and ADP phosphorylation. Accumulating evidence proves that partial uncoupling protects cells against multiple deleterious insults. Type II diabetes is the most common form of metabolic disorder resulting from the development of insulin resistance. Most current treatments ameliorate the hyperglycemic symptom of the disease; however, they are not effective in correcting the underlying cause. Ectopic accumulation of lipid inside liver cells is one leading causal factor for insulin resistance. Mitochondrial uncoupling is known to reduce energy efficiency and increase mitochondrial oxidation; in theory, it may ameliorate intracellular lipid accumulation. Niclosamide is an FDA approved anthlemintic drug that uncouples mitochondria of parasitic worms. In the present study, we showed that niclosamide ethanolamine salt (NEN) is active in uncoupling mammalian mitochondria at high nanomolar concentrations. Oral NEN increases basal energy expenditure and reduces respiration quotient in mice. It is efficacious in preventing and treating high-fat diet induced hepatic steatosis and hyperglycemia. It also improves insulin sensitivity and overall glycemic control in diabetic db/db mice. Our results support that safe mitochondrial uncouplers, such as niclosamide salts, could be potentially developed as new therapies for type II diabetes.


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