Leaky mitochondria make you lose weight - Mitochondrial uncoupling as a treatment for obesity

http://onlinelibrary.wiley.com/doi/10.1046/j.1467-789X.2001.00043.x/pdf

In the 1930s, DNP (2,4-dinitrophenol) was introduced as a drug to treat obesity. What does DNP do? It causes mitochondrial uncoupling, i.e. it increases proton leak and as a result energy production becomes less efficient. Patients treated with DNP therefore 'waste' more energy and metabolic rate increases. An increase in energy output, while keeping the energy intake constant, means that people will start losing weight.

How does DNP work exactly? DNP is a lipid-soluble weak acid. It can pick up protons which it then carries to the other side of the membrane.  It then drops the proton, crosses the membrane again, picks up another proton, etc..


Patients treated with DNP reported feelings of warmth and increased sweating. Doses of 5 mg/kg were tolerated well and there was no increase in heart rate. Patients receiving daily  doses of 3-5 mg/kg experienced a 40% increase in metabolic rate that was maintained for at least 10 weeks. After those 10 weeks, a mean weight loss of 7.8 kg was observed. There was no need for additional dieting.

The increase in metabolic rate was clearly dependent on increase in DNP dose with an average increase of 11% for each dosage increment of 0.1g of DNP.

Because of this success, the drug became popular and it was used more and more. By 1934, about 100,000 people had been treated with the drug. However, the drug was used by inexperienced physicians who had no access to metabolic rate measurements to determine optimal doses. This led to several people being `literally cooked to death' and the drug was taken off the market (there are reports, however, that the drug is still prescribed by US clinics).

Update
The drug can be ordered online and is still responsible for several deaths each year. In 2015 and 2016, 5 and 2 people died in England & Wales from taking DNP, respectively [1]. Interpol and the NHS have been issuing warnings against DNP [2, 3].
Our take-home message: do not mess with your mitochondria and stay away from DNP!

[1] https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/adhocs/007648numberofdeathswheredinitrophenoldnpwasmentionedonthedeathcertificateenglandandwales2007to2016
 
[2] https://www.wada-ama.org/en/media/news/2015-05/interpol-issues-global-alert-for-potentially-lethal-illicit-diet-drug

[3] https://www.nhs.uk/news/medication/new-warnings-issued-over-deadly-dnp-diet-drug/