title: The chemical uncoupler 2,4-dinitrophenol (DNP) protects against diet-induced obesity and improves energy homeostasis in mice at thermoneutrality.
abstract: 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.
authors.affiliation: From the Diabetes, Endocrinology, and Obesity Branch and.
authors.forename: Margalit
authors.initials: M
authors.lastname: Goldgof
authors.affiliation: From the Diabetes, Endocrinology, and Obesity Branch and.
authors.forename: Cuiying
authors.initials: C
authors.lastname: Xiao
authors.affiliation: the Mouse Metabolism Core, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Chanturiya
authors.affiliation: the Mouse Metabolism Core, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: William
authors.initials: W
authors.lastname: Jou
authors.affiliation: the Mouse Metabolism Core, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.affiliation: From the Diabetes, Endocrinology, and Obesity Branch and marc.reitman@nih.gov.
authors.forename: Marc L
authors.initials: ML
authors.lastname: Reitman
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology*; D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000473:pathology; D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects*; D004032:Diet / Q000009:adverse effects*; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D007473:Ion Channels / Q000096:biosynthesis; D051379:Mice; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014475:Uncoupling Agents / Q000494:pharmacology*; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604372:Ucp1 protein, mouse; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D019297:2,4-Dinitrophenol
keywords: 2,4-Dinitrophenol; Adipocyte; Brown Adipose Tissue; CL316243; Drug Development; Energy Metabolism; Obesity; Thermoneutrality; Thermoregulation; Uncoupling Protein