Mitochondrial uncoupling as a target for drug development for the treatment of obesity.
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.
MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK.
J A
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Harper
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Dickinson
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Brand
D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001481:Basal Metabolism / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007473:Ion Channels; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins; D009765:Obesity / Q000188:drug therapy* / Q000503:physiopathology; D000071256:Uncoupling Protein 1; D015431:Weight Loss
D019440:Anti-Obesity Agents; D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1