The Chemical Uncoupler 2,4-Dinitrophenol (DNP) Protects against Diet-induced Obesity and Improves Energy Homeostasis in Mice at Thermoneutrality
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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.
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DNP's effect on obesity seems to be dependent on environmental temperature in mice.
“For instance, DNP’s effect on obesity seems to be dependent on environmental temperature, a well-known phenomenon in mice.”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [269]
Food consumption of mice housed at 22 °C was higher than at 30 °C, which could counter-balance the effect of DNP.
“Interestingly, food consumption of mice housed at 22 °C was higher than at 30 °C, which could counter-balance the effect of DNP [269].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [269]
DNP induces a decrease in energy expenditure by 17% and weight loss by 23% at 30 °C in female C57BL/6J mice.
“Indeed, DNP induces a decrease in energy expenditure by 17% and weight loss by 23% at 30 °C in female C57BL/6J, while no significant effect has been observed at 22 °C [269].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [269]
No significant effect of DNP on obesity has been observed at 22 °C in female C57BL/6J mice.
“Indeed, DNP induces a decrease in energy expenditure by 17% and weight loss by 23% at 30 °C in female C57BL/6J, while no significant effect has been observed at 22 °C [269].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [269]
In high-fat-diet-fed mice, 2,4-dinitrophenol improves metabolic parameters including reduced body weight, improved glucose homeostasis, decreased serum insulin, and decreased liver triglycerides.
“Mice fed a high-fat diet have improved metabolic parameters, such as reduced body weight, improved glucose homeostasis, decreased serum levels of insulin and decreased liver levels of triglycerides264,265.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [265]
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- Authors
- Goldgof, M., Xiao, C., Chanturiya, T., Jou, W., Gavrilova, O., & Reitman, M. L.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Reitman, Marc L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 289
- Issue
- 28
- Pages
- 19341-19350
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4094046
- OpenAlex
- W2056400389
- Cited by
- 138
- References
- 52
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 12 · 2023: 16 · 2022: 13 · 2021: 12 · 2020: 17 · 2019: 6 · 2018: 14 · 2017: 9 · 2016: 10 · 2015: 10 · 2014: 1
- FWCI
- 6.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK075062, DK075063)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- 2,4-dinitrophenol, diet-induced obesity, energy homeostasis, energy expenditure, thermoneutrality, brown adipose tissue thermogenesis, UCP1, glucose tolerance, hepatic steatosis, thyroid hormones, anti-obesity drugs, high-fat diet, fat mass
- MeSH terms
- Uncoupling Protein 1, Animals, Body Temperature Regulation, Adipose Tissue, Brown, Diet, Eating, Energy Metabolism, Gene Expression Regulation, Ion Channels, Obesity, Uncoupling Agents, 2,4-Dinitrophenol, Mitochondrial Proteins, Adiposity, Mice
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