Mitochondrial uncoupling as a target for drug development for the treatment of obesity.

Harper, J. A.; Dickinson, K.; Brand, M. D.

doi:10.1046/j.1467-789x.2001.00043.x

Cited by 250Adipose Tissue and MetabolismMitochondrial Function and PathologyPharmacology and Obesity Treatment

Mitochondrial uncoupling as a target for drug development for the treatment of obesity.

Harper, J. A., Dickinson, K., Brand, M. D.·2001·Obesity Reviews

DOI 10.1046/j.1467-789x.2001.00043.x

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Abstract

Mitochondrial proton cycling is responsible for a significant proportion of basal or standard metabolic rate, so further uncoupling of mitochondria may be a good way to increase energy expenditure and represents a good pharmacological target for the treatment of obesity. Uncoupling by 2,4-dinitrophenol has been used in this way in the past with notable success, and some of the effects of thyroid hormone treatment to induce weight loss may also be due to uncoupling. Diet can alter the pattern of phospholipid fatty acyl groups in the mitochondrial membrane, and this may be a route to uncoupling in vivo. Energy expenditure can be increased by stimulating the activity of uncoupling protein 1 (UCP1) in brown adipocytes either directly or through beta 3-adrenoceptor agonists. UCP2 in a number of tissues, UCP3 in skeletal muscle and the adenine nucleotide translocase have also been proposed as possible drug targets. Specific uncoupling of muscle or brown adipocyte mitochondria remains an attractive target for the development of antiobesity drugs.

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Gain-of-function studies in mice where ectopic expression of UCPs mitigate diet-induced obesity support the notion that uncoupling could be sufficient.
“Gain-of-function studies in mice where ectopic expression of UCPs mitigate diet-induced obesity support the notion that uncoupling could be sufficient (183, 184).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [184]

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What we talk about when we talk about fat
Rosen, E. D., & Spiegelman, B. M. (2014) · Cell · doi:10.1016/j.cell.2013.12.012 · Cited by 2,373 · see citing works
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The role of mitochondria in the pathogenesis of type 2 diabetes
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Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma
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The Regulation and Physiology of Mitochondrial Proton Leak
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2,4-Dinitrophenol (DNP): A Weight Loss Agent with Significant Acute Toxicity and Risk of Death
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Intracellular Coenzymes as Natural Biomarkers for Metabolic Activities and Mitochondrial Anomalies
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Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity
da Silva, C. C. C., Cerqueira, F. M., Barbosa, L. F., de Medeiros, M. H. G., & Kowaltowski, A. J. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2008.00407.x · Cited by 346 · see citing works
Niclosamide ethanolamine–induced mild mitochondrial uncoupling improves diabetic symptoms in mice
Tao, H., Zhang, Y., Zeng, X., Shulman, G. I., & Jin, S. (2014) · Nature Medicine · doi:10.1038/nm.3699 · Cited by 288 · see citing works
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He, Z., Ning, N., Zhou, Q., Khoshnam, S. E., & Farzaneh, M. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.11.005 · Cited by 269 · see citing works
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Variation in the link between oxygen consumption and ATP production, and its relevance for animal performance
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Physiological aspects of energy metabolism and gastrointestinal effects of carbohydrates
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A fundamental system of cellular energy homeostasis regulated by PGC-1α
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The basal proton conductance of skeletal muscle mitochondria from transgenic mice overexpressing or lacking uncoupling protein-3
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Self-citation
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Endothelial Dysfunction: From Molecular Mechanisms to Measurement, Clinical Implications, and Therapeutic Opportunities
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A carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species
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Mitochondrial oxidative stress and the metabolic syndrome
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Three-Dimensional Cell Culture-Based Screening Identifies the Anthelmintic Drug Nitazoxanide as a Candidate for Treatment of Colorectal Cancer
Senkowski, W., Zhang, X., Olofsson, M. H., Isacson, R., Höglund, U., Gustafsson, M. G., Nygren, P., Linder, S. T., Larsson, R. L., & Fryknäs, M. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0792 · Cited by 142 · see citing works
Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice
Alexopoulos, S. J., Chen, S.-Y., Brandon, A. E., Salamoun, J. M., Byrne, F. L., Garcia, C. J., Beretta, M., Olzomer, E. M., Shah, D. P., Philp, A. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16298-2 · Cited by 137 · see citing works
Mitochondrial Dynamics in Diabetic Cardiomyopathy
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The mitochondrial uncoupler 2,4‐dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia
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Mitochondrial Uncoupling as a Therapeutic Target Following Neuronal Injury
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The efficiency of cellular energy transduction and its implications for obesity
Harper, M.-E., Green, K., & Brand, M. D. (2008) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.28.061807.155357 · Cited by 121 · see citing works
Uncoupling protein-2 and cancer
Baffy, G. (2009) · Mitochondrion · doi:10.1016/j.mito.2009.12.143 · Cited by 119 · see citing works
Hyperglycemia-Induced Reactive Oxygen Species and Impaired Endothelial Progenitor Cell Function
Callaghan, M. J., Ceradini, D. J., & Gurtner, G. C. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.1476 · Cited by 114 · see citing works
Acute Stimulation of White Adipocyte Respiration by PKA-Induced Lipolysis
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Mechanisms linking obesity, inflammation and altered metabolism to colon carcinogenesis
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Inhibition of ROS production through mitochondria-targeted antioxidant and mitochondrial uncoupling increases post-thaw sperm viability in yellow catfish
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Arctigenin, a natural compound, activates AMP-activated protein kinase via inhibition of mitochondria complex I and ameliorates metabolic disorders in ob/ob mice
Huang, S., Yu, R.-T., Gong, J., Feng, Y., Dai, Y.-L., Hu, F., Hu, Y., Tao, Y.-D., & Leng, Y. (2011) · Diabetologia · doi:10.1007/s00125-011-2366-3 · Cited by 104 · see citing works
New therapeutic approaches for the treatment of obesity
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Important Trends in UCP3 Investigation
Pohl, E. E., Rupprecht, A., Macher, G., & Hilse, K. E. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00470 · Cited by 102 · see citing works
Canine obesity – an overview
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Bone morphogenetic protein 7: A broad-spectrum growth factor with multiple target therapeutic potency
Boon, M. R., van der Horst, G., van der Pluijm, G., Tamsma, J. T., Smit, J. W. A., & Rensen, P. C. N. (2011) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2011.08.001 · Cited by 99 · see citing works
Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers
Antonenko, Y. N., Avetisyan, A. V., Cherepanov, D. A., Кнорре, Д. А., Korshunova, G. A., Маркова, О. В., Ojovan, S. M., Perevoshchikova, I. V., Pustovidko, A. V., Rokitskaya, T. I., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.212837 · Cited by 98 · see citing works
Effect of mitochondrial uncouplers niclosamide ethanolamine (NEN) and oxyclozanide on hepatic metastasis of colon cancer
Alasadi, A., Chen, M. J., Swapna, G. V. T., Tao, H., Guo, J., Collantes, J. C., Fadhil, N. M., Montelione, G. T., & Jin, S. V. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0092-6 · Cited by 94 · see citing works
Mitochondrial H + Leak and Thermogenesis
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Gene expression in human brown adipose tissue
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The Obesity Epidemic: Current and Future Pharmacological Treatments
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Polyunsaturated Fatty Acids Attenuate Diet Induced Obesity and Insulin Resistance, Modulating Mitochondrial Respiratory Uncoupling in Rat Skeletal Muscle
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NEAT – non‐exercise activity thermogenesis – egocentric & geocentric environmental factors vs. biological regulation
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Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing
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Decreased mitochondrial metabolic requirements in fasting animals carry an oxidative cost
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RNA splicing and editing modulation of 5-HT2C receptor function: relevance to anxiety and aggression in VGV mice
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Variation in Metabolic Rate among Individuals Is Related to Tissue-Specific Differences in Mitochondrial Leak Respiration
Salin, K., Auer, S. K., Rudolf, A. M., Anderson, G. J., Selman, C., & Metcalfe, N. B. (2016) · Physiological and Biochemical Zoology · doi:10.1086/688769 · Cited by 76 · see citing works
Non-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice
Miranda, C. L., Johnson, L. A., de Montgolfier, O., Elias, V. D., Ullrich, L. S., Hay, J. J., Paraiso, I. L., Choi, J., Reed, R. L., Revel, J. S., et al. (2018) · Scientific Reports · doi:10.1038/s41598-017-18992-6 · Cited by 74 · see citing works
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Authors: Harper, J. A., Dickinson, K., & Brand, M. D.
Affiliations: University of Cambridge (GB)
MRC Mitochondrial Biology Unit (GB)
Corresponding author: Brand, M. D.
ORCID: Brand, M. D.
Venue: Obesity Reviews
Publisher: Wiley
Published: 2001-11
Volume: 2
Issue: 4
Pages: 255-265
ISSN: 1467-7881 (ISSN-L)
1467-789X
DOI: 10.1046/j.1467-789x.2001.00043.x
OpenAlex: W1979144331
Cited by: 250
References: 119
Citations by year: 2026: 2 · 2025: 1 · 2024: 6 · 2023: 9 · 2022: 7 · 2021: 6 · 2020: 19 · 2019: 9 · 2018: 12 · 2017: 9 · 2016: 11 · 2015: 19 · 2014: 25 · 2013: 12 · 2012: 15
FWCI: 0.53
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 2440 d)
Locations: Obesity Reviews (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
Keywords: mitochondrial uncoupling, obesity treatment, energy expenditure, UCP1, brown adipocytes, beta3-adrenergic agonists, UCP2, UCP3, adenine nucleotide translocase, 2,4-dinitrophenol, thyroid hormones, mitochondrial membrane phospholipids, anti-obesity drugs
MeSH terms: Uncoupling Protein 1, Basal Metabolism, Carrier Proteins, Energy Metabolism, Humans, Ion Channels, Membrane Proteins, Mitochondria, Obesity, Weight Loss, Anti-Obesity Agents, Mitochondrial Proteins

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Mitochondrial uncoupling as a target for drug development for the treatment of obesity.

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