When scientists genetically engineered mice so that they could not generate an amino acid called cysteine, and then fed the mice a diet without any cysteine in it, the mice lost 30% of their body weight in one week. This study has suggested that the loss of cysteine interferes with metabolic pathways in mammals, so that instead of using food to generate energy, the body starts burning fat stores in an attempt to supply the body with energy. The findings have been reported in Nature.
Cysteine is present in almost all foods, so this is not a recommendation to stop eating cysteine if you want to lost weight. The findings have also not been confirmed in humans. But they do reveal more about metabolism, and may help open up new avenues for weight loss.
This research has provided new insights into how mammals can process molecules in food like carbohydrates and fats, and how the loss of cysteine impacts cells. The scientists found, for example, that low cysteine levels cause a decrease in co-factor coenzyme A (CoA) levels. CoA is important to more than 100 metabolic reactions in the body, and is a co-factor for many enzymes. Mice that do not produce CoA don't live past about three weeks of life.
This work has revealed more about CoA in adult mice, however. When cysteine gets low, and CoA levels drop, it seems to disrupt pathways that convert carbs and fats into energy.
“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 A. Nudler, Ph.D., a Professor at NYU Grossman School of Medicine, and Howard Hughes Medical Institute (HHMI) investgator. “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."
While cysteine removal is not feasible or safe for people, the researchers noted that there are far lower levels of cysteine in foods like fruits, legumes, and vegetables, compared to red meat. This research seems to explain, or at least provides one reason why eating less meat is better for health.
Cysteine deprivation was also found to interfere with a process that produces the essential cellular fuel source: adenosine triphosphate (ATP). This process involves oxidative phosphorylation, which requires CoA. As such, many other molecules weren't used in those reactions and were lost in urine instead, such as pyruvate and citrate. The body then turned to stored fat to produce energy.
Cysteine restriction had other effects too; it triggered both the integrated stress response (ISR) and oxidative stress response (OSR). This simultaneous ISR and OSR pathway activation has only been observed in cancer cells before this. But normal tissues triggered these major stress response pathways in response to the loss of cysteine. The stress hormone GDF15 was generated by these pathways, which prevented the restoration of fat stores, and made the cysteine-free mice lose even more weight.
“We hope in the future to hijack parts of this process to induce a similar weight loss in humans but without completely removing cysteine,” said co-senior study author Dan R. Littman, M.D., Ph.D., a Professor at NYU Grossman School of Medicine and HHMI investigator.
Sources: NYU Langone, Nature