The Quest to Burn Fat, Effortlessly and Safely
The quest to burn fat, effortlessly and safely | Science
Treatment of obesity and obesity-associated diseases has been challenging, with the first potential cure claimed in 1934 with the protonophore 2,4-dinitrophenol (DNP). This chemical dissipates mitochondrial membrane potential into heat production and is extremely effective in boosting metabolic rate and promoting weight loss. However, severe side effects, including cataract formation, cardiotoxicity, overheating, and death, prevented its further use.
In a recent study, Long et al. report that a secreted enzyme called peptidase M20 domain containing 1 (PM20D1) converts fatty acids and amino acids into N-acyl amino acids, which directly uncouple mitochondrial membrane potential in a way similar to that of DNP, to increase energy expenditure without physical movement. http://www.cell.com/cell/abstract/S0092-8674(16)30675-4
Might these endogenous metabolites be a safe alternative to chemical uncouplers, facilitating effortless fat burning without a fatal consequence?
…
The study of Long et al. reawakens the promise of chemical-based mitochondrial uncoupling as a therapeutic strategy for obesity and obesity-associated diseases. Recent progress has been made toward developing liver-specific DNP derivatives or milder mitochondrial uncouplers that are effective in treating obesity and obesity-associated diseases but with minimal side effects.
The identification of N-acyl amino acids as endogenous mitochondrial uncouplers would not only advance our understanding of adaptive thermogenesis, but also might present safer alternatives to chemical uncouplers if a direct role of N-acyl amino acids as mitochondrial uncouplers can be established. This may require the development of N-acyl amino acid mimetics, given the higher hydrolase over synthase activity of PM20D1.
An immediate question that should be addressed is that in cell culture, N-acyl amino acids take 20 to 40 min to initiate uncoupling, which is much longer than the time taken by known chemical uncouplers such as DNP. In addition, N-acyl amino acids such as N-arachidonyl glycine (C20:4-Gly) have a wide range of biological functions via their interactions with G protein–coupled receptors and ion channels in brain and other tissues, which in vivo could contribute appreciably to the food suppression and weight-loss phenotypes observed in the treated mice.
Furthermore, because the uncoupling effect of N-acyl amino acids is UCP1-independent and thus not limited to brown and beige fat, their role in mitochondrial ATP production in highly energetic tissues such as heart, brain, and kidney needs to be explored.
The findings of Long et al. open a door on a new class of endogenous mitochondrial uncouplers and present a new mechanism of adaptive thermogenesis via a secreted enzyme and its products. However, every open door reveals more questions than it answers, and follow-up studies are required. We are left to ponder the hope of a magic pill offering effortless and consequence-free fat burning.
Mitochondrial uncoupling and thermogenesis N-Acyl amino acids are generated from free fatty acids and amino acids by the enzyme PM20D1, which is secreted by adipocytes in fat tissue. The N-acyl amino acids act as mitochondrial uncouplers, thereby boosting energy expenditure, but it is not yet clear in which tissues this occurs.
The quest to burn fat, effortlessly and safely | Science
Treatment of obesity and obesity-associated diseases has been challenging, with the first potential cure claimed in 1934 with the protonophore 2,4-dinitrophenol (DNP). This chemical dissipates mitochondrial membrane potential into heat production and is extremely effective in boosting metabolic rate and promoting weight loss. However, severe side effects, including cataract formation, cardiotoxicity, overheating, and death, prevented its further use.
In a recent study, Long et al. report that a secreted enzyme called peptidase M20 domain containing 1 (PM20D1) converts fatty acids and amino acids into N-acyl amino acids, which directly uncouple mitochondrial membrane potential in a way similar to that of DNP, to increase energy expenditure without physical movement. http://www.cell.com/cell/abstract/S0092-8674(16)30675-4
Might these endogenous metabolites be a safe alternative to chemical uncouplers, facilitating effortless fat burning without a fatal consequence?
…
The study of Long et al. reawakens the promise of chemical-based mitochondrial uncoupling as a therapeutic strategy for obesity and obesity-associated diseases. Recent progress has been made toward developing liver-specific DNP derivatives or milder mitochondrial uncouplers that are effective in treating obesity and obesity-associated diseases but with minimal side effects.
The identification of N-acyl amino acids as endogenous mitochondrial uncouplers would not only advance our understanding of adaptive thermogenesis, but also might present safer alternatives to chemical uncouplers if a direct role of N-acyl amino acids as mitochondrial uncouplers can be established. This may require the development of N-acyl amino acid mimetics, given the higher hydrolase over synthase activity of PM20D1.
An immediate question that should be addressed is that in cell culture, N-acyl amino acids take 20 to 40 min to initiate uncoupling, which is much longer than the time taken by known chemical uncouplers such as DNP. In addition, N-acyl amino acids such as N-arachidonyl glycine (C20:4-Gly) have a wide range of biological functions via their interactions with G protein–coupled receptors and ion channels in brain and other tissues, which in vivo could contribute appreciably to the food suppression and weight-loss phenotypes observed in the treated mice.
Furthermore, because the uncoupling effect of N-acyl amino acids is UCP1-independent and thus not limited to brown and beige fat, their role in mitochondrial ATP production in highly energetic tissues such as heart, brain, and kidney needs to be explored.
The findings of Long et al. open a door on a new class of endogenous mitochondrial uncouplers and present a new mechanism of adaptive thermogenesis via a secreted enzyme and its products. However, every open door reveals more questions than it answers, and follow-up studies are required. We are left to ponder the hope of a magic pill offering effortless and consequence-free fat burning.
Mitochondrial uncoupling and thermogenesis N-Acyl amino acids are generated from free fatty acids and amino acids by the enzyme PM20D1, which is secreted by adipocytes in fat tissue. The N-acyl amino acids act as mitochondrial uncouplers, thereby boosting energy expenditure, but it is not yet clear in which tissues this occurs.
