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.