New mechanism rewires cell energy processing for weight loss, shows study

Led by researchers at NYU Grossman School of Medicine, the study reveals key details about how cells process fuels like carbohydrates and fats, and how cysteine depletion affects tissues

Mice genetically engineered to lack the ability to make the amino acid cysteine, and fed a cysteine-free diet, lost 30 per cent of their body weight in just one week, a new study shows.

Published online May 21 in Nature, the work found that cysteine depletion disrupts the normal metabolic pathways mammalian cells use to convert food into energy, forcing the animals to rapidly burn fat stores in a futile attempt to meet energy demands.

Led by researchers at NYU Grossman School of Medicine, the study reveals key details about how cells process fuels like carbohydrates and fats (metabolism), and how cysteine depletion affects tissues. 

 

Experiments showed that lowering cysteine levels caused a drop in levels of the small molecule called coenzyme A (CoA), which rendered inefficient mechanisms that convert carbohydrates and fats into energy.

Despite CoA being involved in more than 100 intermediate metabolic reactions and serving as a partner (cofactor) for 4% of all enzymes in the body, scientists had previously been unable to study its function directly.

This is because mice with defective CoA synthesis typically do not survive beyond three weeks of age. The current findings detail, for the first time, how CoA shapes metabolism in adult mice. 

 

"Our surprising findings reveal that low cysteine levels triggered rapid fat loss in our study mice by activating a network of interconnected biological pathways," said co-senior study author Evgeny Nudler, PhD, the Julie Wilson Anderson Professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine, and an investigator with the Howard Hughes Medical Institute.

"While driving weight loss in the clinic remains a key future mission, we are most excited for the moment about the profound, fundamental aspects of metabolism revealed in this study," added Dr. Nudler. 

 

The current finding does not immediately suggest a new approach to weight loss, the authors caution, as cysteine is found in nearly all foods.

Achieving a truly cysteine-free diet would require patients to consume a specially formulated solution that would be challenging for most.

Moreover, because cysteine is involved in numerous cellular pathways, eliminating it -- such as through a drug that inhibits cysteine production -- could make organs more vulnerable to everyday toxins, including medications.

That said, the study authors say it is worth considering that fruits, vegetables, and legumes contain much lower levels of cysteine and its precursor, the sulfur-containing amino acid methionine, than red meat.