Cutting a single amino acid from the diet caused rapid, drastic weight loss in mice by converting white fat into calorie-burning brown fat. The study reveals a powerful new mechanism for weight loss that doesn’t rely on eating less and moving more.
When we think of “body fat,” we’re most likely thinking of white fat, which stores energy from the food we eat and builds up when we take in more calories than we burn. White fat has been linked to health problems like heart disease and diabetes. Brown fat, on the other hand, is much more beneficial. It burns energy instead of storing it, producing heat to keep our bodies warm in a process called thermogenesis.
Scientists are especially interested in brown fat because increasing its activity, or converting white fat into brown-like fat, could help people burn more calories and improve overall health. A new study has found that reducing the amino acid cysteine triggers the transition of white fat cells to brown fat cells and can lead to significant weight loss.
“In addition to the dramatic weight loss and increase in fat burning resulting from the removal of cysteine, … [t]hese results suggest future weight management strategies that might not rely exclusively on reducing caloric intake,” said study co-author Krisztian Stadler, PhD, a professor at the Pennington Biomedical Research Center (PBRC), affiliated with Louisiana State University.
Cysteine is a “proteinogenic” amino acid, meaning it’s involved in making proteins, in addition to diverse metabolic functions. The body can produce cysteine, making it a non-essential amino acid (essential amino acids have to be obtained through diet). In the present study, the researchers explored how cysteine affected metabolism, fat tissue behavior, and body weight by examining how cysteine influences metabolic changes seen in both humans and mice.
They looked at evidence obtained from the CALERIE-II trial, a two-year randomized controlled trial investigating the effects of long-term calorie restriction in healthy, non-obese adults. As part of the trial, participants reduced their calorie intake by an average of 14% over two years. The researchers found that the reduced caloric intake led to a drop in cysteine levels and changes in metabolic pathways related to cysteine and the essential amino acid methionine.
Mice that had been genetically engineered to lack the enzyme CTH that helps produce cysteine from methionine were fed a cysteine-free diet. The mice experienced rapid and drastic weight loss, losing around 25% to 30% of their body weight within one week, primarily due to fat loss. Reintroducing cysteine to the animals’ diet reversed the weight loss, showing the effect was specifically due to cysteine deprivation. The researchers noted that cysteine deficiency caused white fat tissue to convert into brown-like fat, a process known as “browning.” This transition increased energy expenditure and fat burning without requiring changes in food intake or activity levels.
The researchers then examined the impact of cysteine deficiency on diet-induced obesity. When obese mice that had been fed a high-fat diet for 12 weeks were switched to a low-cysteine diet, they lost approximately 30% of their body weight in a week despite maintaining a high calorie intake. The animals also had improved blood sugar control, increased energy expenditure, and reduced inflammation in fat tissue. Analysis of the mice’s fat tissue revealed browning.
“Reverse translation of human caloric restriction trial identified a new player in energy metabolism,” said co-author Eric Ravussin, PhD, who holds the Douglas L Gordon Chair in Diabetes and Metabolism at PBRC and oversees its Human Translational Physiology Laboratory. “Systemic cysteine depletion in mice causes weight loss with increased fat utilization and browning of adipocytes [fat cells].”
Interestingly, the fat tissue browning response observed by the researchers didn’t rely on UCP1, a common thermogenic protein, suggesting a new, independent mechanism. Instead, the effect required noradrenaline signaling through part of the sympathetic nervous system, which is primarily responsible for the body’s fight-or-flight response. Noradrenaline, a hormone and neurotransmitter that’s also known as norepinephrine, plays a key role in this response.
The study has some limitations. The mouse models used were genetically modified, which is understandable, but which may not reflect human metabolism. The severity of weight loss in mice was extreme and potentially lethal, making it non-translatable as-is to humans. The exact UCP1-independent thermogenesis pathway remains unknown. It’s not yet known how safe or effective cysteine manipulation would be in humans. The study doesn’t address the long-term effects or sustainability of cysteine depletion.
Nevertheless, its findings suggest that cysteine plays a key role in regulating energy metabolism and fat storage. It highlights a potential new drug target for obesity treatment, particularly by mimicking the effects of cysteine depletion without actually depleting cysteine, which could be dangerous. The bottom line is that the study provides further support for the notion that the amino acid composition, not just calories, can influence healthspan and weight regulation.
The study was published in the journal Nature Metabolism.
