September 30, 2020
The French used 2,4-Dinitrophenol (DNP) in the manufacturing of munitions during the First World War. Since then, DNP has been used as a dye, wood preservative, herbicide, and photograph developer. It was noticed from these uses that workers who came in contact with the molecule would lose weight and, in the early nineteen-thirties, DNP was commercialized to increase metabolism and burn fat (a complete review DNP and its history can be found here). DNP was shown to cause weight loss by decreasing the formation of high-energy phosphate bonds in mitochondria while at the same time stimulating systemic oxygen consumption — a combination known as uncoupling oxidative phosphorylation. On the positive side, this uncoupling leads to a heightened metabolic rate and increased fat metabolism. However, in the presence of DNP, the flux of protons through the mitochondrial membrane produced heat, but not ATP. This excess heat production led to uncontrolled hyperthermia following failed mechanisms of thermoregulatory homeostasis which resulted in significant morbidity and mortality. As a result, DNP was removed from the market in 1938, though it has periodically been sold through private clinics and over the Internet despite its evident toxicity.
While our understanding of fat metabolism has evolved considerably since the nineteen-thirties, blockbuster agents have yet to be developed to help curb the obesity epidemic. Three areas of current interest in the search for control over fat metabolism are:
1/ Absorption & Production
As described in a review article published last year, the gut microbiome has been shown to have a major impact on dietary lipid composition, digestion, and absorption, potentially altering intestinal lipoprotein formation. It is notable that production of triglycerides (which are stored in adipose tissues) comes in large part from metabolism of carbohydrates through de novo lipogenesis rather than by the recycling of fatty acids, highlighting the impact of both excess fatty acids and excess carbohydrates in modern diets.
Identification of brown adipose tissues as a thermogenic organ in 1961 showed that some specific adipose tissues which were rich in mitochondria could reproduce the effect of DNP through the regulation of uncoupling protein 1 (UCP1). Since then, the search for the mechanisms to switch from white adipocytes to brown adipocytes for fat storage has explored both natural (through cold exposure and exercise) and pharmacological approaches. The latest attempt to switch from white to brown adipocytes uses a CRISPR cassette ex vivo. The cells are then transplanted back into the animal reducing risk of obesity and metabolic disease.
Fat, stored in form of triglycerides, is catabolized between meals as a prime energy source. As mentioned above, the search for safe ways to increase the metabolic rate has been a focus of research for many decades. It is now accepted that indiscriminately trying to activate mitochondrial uncoupling brings unavoidable toxicity. Although a narrower approach to drug UCP1 is underway, the identification of safe and effective agents remains a challenge. It is hoped that a better understanding of the mechanisms controlling mitochondrial uncoupling will offer alternative targets to UCP1 and better ways to drug this tricky protein.
We also hope that continued investment in understanding the underlying details of fat metabolism will eventually lead to better choices for consumers and patients in managing their weight and overall health.
– Jonathan Friedlander, PhD & Geoffrey W. Smith
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