Cysteine restriction plays key role in weight loss
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Cysteine restriction plays key role in weight loss
Cysteine, an amino acid, may play a key role in metabolic health and weight control. A diet that’s low in the amino acid cysteine reprograms fat to burn more calories, triggering weight loss and reduced inflammation. The findings hint at strategies to improve metabolic health without restricting calories. Researchers found substantial changes in study participants’ fat metabolomes after a year of calorie restriction and weight loss. A careful look at those changes revealed that calorie restriction came with an unexpected consequence. The researchers also saw changes in a metabolic pathway to make Cysteine. In a related paper in Nature on May 21, 2025, another team looked at weight changes when mice were fed diets lacking individual amino acids. Similar to the study from Dixit’s team, they also found that a low-cysteine diet led to the most weight loss, with animals losing about a third of their body weight in just a week. The team also showed how cy Steine restriction leads to widespread changes in metabolism.
Cysteine restriction plays key role in weight loss
At a Glance Studies in people and mice show a diet that’s low in the amino acid cysteine reprograms fat to burn more calories, triggering weight loss and reduced inflammation.
The findings hint at strategies to improve metabolic health without restricting calories.
Image The amino acid cysteine may play a key role in metabolic health and weight control. CrizzyStudio / Shutterstock
The standard advice for losing weight is to take in fewer calories than you burn through a combination of healthy eating and exercise. Studies have suggested that calorie-restricted diets may also slow aging and delay chronic health conditions to help you live longer.
To examine the effects of a calorie-restricted diet in people, a research team led by Dr. Vishwa Deep Dixit at Yale School of Medicine used an approach called metabolomics. They looked for changes to thousands of metabolites (compounds formed as our bodies break down food and store energy) within fat tissue samples taken from people after a year of calorie restriction and weight loss.
The tissue samples came from participants in a clinical trial called CALERIE, in which healthy young and middle-aged men and women reduced their calorie intake by an average of about 14% over two years. This reduction led to weight loss along with other metabolic benefits, including improved muscle health. Results from the new analysis appeared in Nature Metabolism on June 3, 2025.
The researchers found substantial changes in study participants’ fat metabolomes. A careful look at those changes revealed that calorie restriction came with an unexpected consequence: reduced levels of cysteine. The researchers also saw changes in a metabolic pathway to make cysteine.
To find out if lowering cysteine could lead to weight loss, the researchers created mice that lack the ability to make cysteine and gave them a diet restricted in cysteine but with plenty of calories. The animals lacking cysteine rapidly lost body weight. When cysteine was added back into their diets, the mice put the weight back on.
Further study revealed how low cysteine led to weight loss. The cysteine-deficient diet prompted white fat, which stores energy, to convert into brown fat, which burns energy to produce heat. When obese mice were deprived of cysteine, they showed a rapid browning of their fat as they lost weight. They also had lower levels of inflammation. The researchers found that these changes depended on signals from the sympathetic nervous system, which activates in stressful or dangerous situations.
In a related paper in Nature on May 21, 2025, another team looked at weight changes when mice were fed diets lacking individual amino acids. Similar to the study from Dixit’s team, they also found that a low-cysteine diet led to the most weight loss, with animals losing about a third of their body weight in just a week. The team also showed how cysteine restriction leads to widespread changes in metabolism.
“There’s a pathway in the body that can make cysteine,” Dixit explains. “During abundance it’s normally dormant, but if you’re getting less cysteine from your diet, your body activates this pathway in an effort to make more. And it appears that awakening this dormant pathway produces metabolic and health benefits.”
The findings point to an unexpected role for dietary cysteine and cysteine metabolism in body weight and overall health. They also suggest new strategies for addressing obesity-related health problems that might not involve cutting calories.
—by Kendall K. Morgan, Ph.D.
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References
Cysteine depletion triggers adipose tissue thermogenesis and weight loss. Lee AH, Orliaguet L, Youm YH, Maeda R, Dlugos T, Lei Y, Coman D, Shchukina I, Andhey PS, Smith SR, Ravussin E, Stadler K, Chen B, Artyomov MN, Hyder F, Horvath TL, Schneeberger M, Sugiura Y, Dixit VD. Nat Metab. 2025 Jun 3. doi: 10.1038/s42255-025-01297-8. Epub ahead of print. PMID: 40461845.
Unravelling cysteine-deficiency-associated rapid weight loss. Varghese A, Gusarov I, Gamallo-Lana B, Dolgonos D, Mankan Y, Shamovsky I, Phan M, Jones R, Gomez-Jenkins M, White E, Wang R, Jones DR, Papagiannakopoulos T, Pacold ME, Mar AC, Littman DR, Nudler E. Nature. 2025 May 21. doi: 10.1038/s41586-025-08996-y. Epub ahead of print. PMID: 40399674.
Funding
NIH’s National Institute on Aging (NIA) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Gruber Foundation; National Science Foundation; McCluskey family; Interstellar Initiative (New York Academy of Sciences and Japan Agency for Medical Research and Development).
Research highlights: Cysteine depletion triggers adipose tissue thermogenesis and weight loss
A recent study in Nature Metabolism explores how the amino acid cysteine influences fat metabolism and energy balance. Researchers found that depleting cy Steine in mice led to rapid weight loss, increased fat utilization, and the transformation of white adipose tissue into a thermogenic, or heat-producing, state. The study is significant because it identifies cysteines as a key dietary factor that influences fat. metabolism andEnergy balance. It offers a potential new target for obesity and metabolic disease research. Modulating cysteined intake or depletion could become part of future interventions designed to reduce fat mass and reduce mass. The research highlights the potential of targeting amino acid metabolism as a therapeutic approach for traditional obesity and related conditions. The researchers used a range of antibodies to detect changes in protein expression and signaling pathways. They also used a DAB substrate to visualize UCP1 and possibly other markers. The findings suggest that dietary cystein levels can influence energy balance by modulating adipose. tissue function. This opens up new possibilities for nutritional and pharmacological strategies aimed at promoting weight loss and improving metabolic health.
Overview
The study aimed to understand how specific amino acids, particularly cysteine, affect adipose tissue thermogenesis, the process by which fat cells generate heat by burning calories. While caloric restriction and methionine restriction have been shown to promote longevity and metabolic health, the role of individual amino acids like cysteine in these processes has remained unclear.
Researchers observed that caloric restriction in humans reduces cysteine levels in white adipose tissue. To explore this further, they used mouse models to test how systemic cysteine depletion affects metabolism. The study is significant because it identifies cysteine as a key dietary factor that influences fat metabolism and energy balance, offering a potential new target for obesity and metabolic disease research.
Key findings
The researchers found that depleting cysteine in mice led to rapid weight loss, increased fat utilization, and the transformation of white adipose tissue into a thermogenic, or heat-producing, state. This process, known as “browning,” involves the activation of genes and pathways typically associated with brown fat, which is known for its ability to burn energy.
Interestingly, the weight loss and thermogenesis triggered by cysteine depletion were independent of two well-known metabolic regulators: FGF21 and UCP1. Instead, the effects were driven by the sympathetic nervous system through β3-adrenergic receptor signaling. This pathway is known to stimulate fat breakdown and energy expenditure in response to cold or stress.
In obese mice, cysteine restriction led to a 30% reduction in body weight, improved metabolic health, and reduced inflammation in adipose tissue. These findings suggest that cysteine availability plays a regulatory role in energy metabolism and immune responses.
The role of antibodies
To investigate the molecular mechanisms underlying these effects, the researchers used a range of antibodies to detect changes in protein expression and signaling pathways. Several antibodies from Abcam were instrumental in these experiments:
Anti-UCP1 antibody: This antibody was used to detect uncoupling protein 1 (UCP1), a key marker of thermogenic activity in brown and beige adipose tissue Anti-α-tubulin antibody: Used as a loading control in western blotting. α-tubulin is a cytoskeletal protein that helps normalize protein levels across samples, ensuring that differences in UCP1 or other proteins are not due to unequal loading. Mitochondrial Complex I Activity Assay Kit: Used to measure mitochondrial respiratory activity in adipose tissue, and support findings that cysteine depletion enhances mitochondrial function and energy expenditure. DAB Substrate Kit: Used in immunohistochemistry to visualize UCP1 and possibly other markers. When paired with HRP-conjugated secondary antibodies, the DAB substrate produces a brown stain at the site of antigen-antibody binding, allowing researchers to localize protein expression in tissue sections.
These antibodies were used in western blotting, immunohistochemistry, and immunofluorescence assays to validate the activation of thermogenic pathways and to confirm the presence of key proteins involved in fat metabolism. Their specificity and reliability were essential for accurately interpreting the molecular changes observed in the study.
Implications
The findings suggest that dietary cysteine levels can influence energy balance by modulating adipose tissue function. This opens up new possibilities for nutritional and pharmacological strategies aimed at promoting weight loss and improving metabolic health.
By identifying a mechanism that operates independently of FGF21 and UCP1, the study also broadens our understanding of how thermogenesis can be regulated. This could be particularly relevant for individuals who do not respond to therapies targeting traditional thermogenic pathways.
Moreover, the research highlights the potential of targeting amino acid metabolism as a therapeutic approach for obesity and related conditions. Modulating cysteine intake or mimicking its depletion could become part of future interventions designed to enhance energy expenditure and reduce fat mass.
Future work
Future studies will likely explore how cysteine metabolism interacts with other dietary components and metabolic pathways. Researchers may also investigate whether similar effects can be observed in humans and whether cysteine depletion can be safely and effectively used as a therapeutic strategy.
Ongoing research may focus on:
Identifying small molecules that mimic the effects of cysteine depletion.
Exploring the long-term effects of cysteine restriction on metabolic health.
Investigating how cysteine levels influence immune cell function in adipose tissue.
Testing whether cysteine modulation can enhance the effects of existing weight-loss therapies.
These directions could help translate the findings from animal models into clinical applications and deepen our understanding of the links between diet, metabolism, and immune function.
References
Lee, A.H., Orliaguet, L., Youm, YH. et al. Cysteine depletion triggers adipose tissue thermogenesis and weight loss. Nat Metab (2025).
Source: https://www.nih.gov/news-events/nih-research-matters/cysteine-restriction-plays-key-role-weight-loss