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J Biol Chem. 2014 Jul 11;289(28):19341-50. doi: 10.1074/jbc.M114.568204. Epub 2014 May 28.

The chemical uncoupler 2,4-dinitrophenol (DNP) protects against diet-induced obesity and improves energy homeostasis in mice at thermoneutrality.

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  • 1From the Diabetes, Endocrinology, and Obesity Branch and.
  • 2the Mouse Metabolism Core, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
  • 3From the Diabetes, Endocrinology, and Obesity Branch and


The chemical uncoupler 2,4-dinitrophenol (DNP) was an effective and widely used weight loss drug in the early 1930s. However, the physiology of DNP has not been studied in detail because toxicity, including hyperthermia and death, reduced interest in the clinical use of chemical uncouplers. To investigate DNP action, mice fed a high fat diet and housed at 30 °C (to minimize facultative thermogenesis) were treated with 800 mg/liter DNP in drinking water. DNP treatment increased energy expenditure by ∼ 17%, but did not change food intake. DNP-treated mice weighed 26% less than controls after 2 months of treatment due to decreased fat mass, without a change in lean mass. DNP improved glucose tolerance and reduced hepatic steatosis without observed toxicity. DNP treatment also reduced circulating T3 and T4 levels, Ucp1 expression, and brown adipose tissue activity, demonstrating that DNP-mediated heat generation substituted for brown adipose tissue thermogenesis. At 22 °C, a typical vivarium temperature that is below thermoneutrality, DNP treatment had no effect on body weight, adiposity, or glucose homeostasis. Thus, environmental temperature should be considered when assessing an anti-obesity drug in mice, particularly agents acting on energy expenditure. Furthermore, the beneficial effects of DNP suggest that chemical uncouplers deserve further investigation for the treatment of obesity and its comorbidities.

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.


2,4-Dinitrophenol; Adipocyte; Brown Adipose Tissue; CL316243; Drug Development; Energy Metabolism; Obesity; Thermoneutrality; Thermoregulation; Uncoupling Protein

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