This paper investigated whether metabolic disease could be improved by mitochondrial uncoupling agents that oxidize hepatic triglyceride. To this end, the authors studied a liver-targeted, methyl ether derivative of 2,4-dinitrophenol; the parent compound is a known weight loss agent but it also induces fatal hyperthermia. In rats that were fed a high-fat diet, the derivative reversed hypertriglyceridaemia, fatty liver disease and insulin resistance, and it decreased hyperglycaemia in a rat model of diabetes. Importantly, hepatic and systemic toxicities were not observed and the derivative did not induce hyperthermia.
References
Perry, R. J. et al. Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metab. 18, 740–748 (2013)
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Harrison, C. Mitochondrial uncoupler blocks metabolic disease. Nat Rev Drug Discov 13, 20 (2014). https://doi.org/10.1038/nrd4212
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DOI: https://doi.org/10.1038/nrd4212