Healthcare (Commonwealth Union) – A newly published study reveals that mice genetically modified to be incapable of producing the amino acid cysteine — and placed on a diet entirely free of it — shed 30 percent of their body weight in only one week.
Appearing in Nature on May 21, the research demonstrates that removing cysteine from the diet disrupts key metabolic systems that mammals use to extract energy from nutrients. As a result, the mice were forced to burn through their fat reserves at a rapid pace in a largely ineffective attempt to meet their energy needs.
Conducted by a team at NYU Grossman School of Medicine, the study offers new insights into how cells metabolize energy sources such as fats and carbohydrates, and how a lack of cysteine impacts biological tissues. The experiments found that depleting cysteine led to a significant reduction in coenzyme A (CoA), a vital molecule that supports the efficient conversion of nutrients into energy.
Although CoA plays a role in over 100 intermediary metabolic processes and partners with around 4 percent of all bodily enzymes, scientists had previously struggled to study its function directly. This was because mice with genetic defects in CoA production typically die before reaching three weeks of age. The new research is the first to illuminate how CoA influences metabolism in mature mice.
Dr. Evgeny A. Nudler, co-senior author of the study, who holds the Julie Wilson Anderson Professorship in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine and is also a researcher at the Howard Hughes Medical Institute indicated that their unexpected discovery shows that reduced levels of cysteine sparked rapid fat loss in our lab mice by setting off a web of interconnected biological processes.
Dr. Nudler further pointed out that although developing clinical strategies for weight loss remains an important long-term goal, what excites them most right now is the deep insight this gives us into the basic workings of metabolism.
The researchers emphasize that this discovery does not point to an immediate new method for weight loss, as cysteine is present in nearly all dietary sources. Completely removing it from the diet would require a specially designed nutritional formula, which would be difficult for most people to maintain. Additionally, because cysteine plays a role in many key cellular functions, reducing its levels—such as through a drug that blocks its production—could increase susceptibility to everyday toxins, including those from medications.
Nevertheless, the researchers note that plant-based foods like fruits, vegetables, and legumes have far lower levels of cysteine and its precursor, the sulfur-based amino acid methionine, than red meat. While previous research has associated diets low in sulfur amino acids with various health benefits, this study highlights that cysteine depletion in particular—not simply methionine reduction—is responsible for those effects.
“Given that achieving maximum cysteine deprivation weight loss in the mice was dependent on both diet and deletion of the gene, moving forward we can now restore cysteine production genetically in specific cells or tissues and determine the role of each in the dramatic weight loss we observed,” explained the co-senior author Dan R. Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Molecular Immunology in the Department of Pathology, and a professor in the Department of Cell Biology, at NYU Grossman School of Medicine. “We hope in the future to hijack parts of this process to induce a similar weight loss in humans but without completely removing cysteine,” added Dr. Littman, who is an investigator with the Howard Hughes Medical Institute as well.
This study is the first to investigate the impact of eliminating cysteine—or any of the nine essential amino acids—which must be acquired through the diet and are crucial for producing proteins that form the majority of the body’s enzymes, tissues, and signaling molecules.
