METADIS: STAY Sulfur amino acids, energy metabolism and obesity

The prevalence of overweight and obesity are increasing worldwide. A new study published in The Lancet in February 2024 shows that more than 1 billion people in the world are now living with obesity, and that 43% of adults were overweight in 2022. Obesity leads to increased risk of chronic diseases and mortality. Over the last few years, two amino acids, methionine and cysteine, have been associated with development of obesity and related metabolic diseases. In rodents, experiments with diets low in methionine and cysteine content result in improved glucose and lipid metabolism and reduced body fat. In the STAY project, we examined the role of cysteine and methionine and related compounds in human metabolic health and obesity. We implemented a dietary intervention study in participants with overweight and obesity to evaluate the effects of a plant-based diet low in methionine and cysteine on body weight, body composition, and energy balance, as well as obesity-related blood markers (glucose and lipid metabolism, amino acids, fatty acids). A total of 61 participants were randomized to the intervention with 55 participants completing the 8-week trial. Data were collected between March 2020 to March 2022. Results show that an 8-week intervention with a sulfur amino acid-restricted, plant-based diet in adults with overweight and obesity led to a decrease in body weight and serum leptin concentrations, and an increase in plasma ketone bodies. The diet also affected plasma and urine sulfur metabolites, and gene expression in white adipose tissue (doi. 10.1186/s12967-023-04833-w.). In addition, we have used data from a large Dutch population study (the Maastricht study) to investigate associations of dietary, circulating and urinary methionine and cysteine with body fat and related metabolic outcomes. The first article (doi: 10.1007/s00394-022-03041-4) shows associations of plasma concentrations of methionine and cysteine with different fat depots; plasma methionine was positively associated with liver fat, while plasma cysteine was associated with greater general, central, and peripheral adiposity. The second paper from the Maastricht study (doi:10.1016/j.tjnut.2023.05.008) shows that a significant dietary determinant of plasma sulfur amino acids was protein intake, particularly from animal sources, which was associated with higher plasma cysteine levels. This project has given us insight into the role of methionine and cysteine in human metabolic health and obesity development.

In obesity management, correction of small positive energy imbalances is a natural target for intervention. Dietary changes towards diets rich in plant-based foods and low in animal-derived foods are likely to substantially benefit human health by reducing morbidity and mortality. Research over the last decade suggests that methionine and cysteine, two dietary sulfur amino acids (SAA) that are abundant in proteins from animal sources, play a role in development of obesity and related metabolic diseases. In mice and rats, dietary restriction of SAA leads to beneficial changes in body composition, insulin sensitivity, energy metabolism and lipid profile. In the STAY project, we aimed to examine whether we can achieve the beneficial findings seen in animal experiments in humans with obesity. By using both interventional and observational data and perform extensive biomarker analyses, we have supported the causal relationship between SAA and body fatness in humans, and expanded the knowledge of the potential mechanisms by which a plant-based diet low in SAA content can benefit metabolic health. The results from the STAY project will further aid in the planning and interpretation of future studies in animals and humans.

Overweight and obesity lead to metabolic disturbances and increase the overall risk of morbidity and mortality. In the past decade, circulating amino acids have become increasingly recognized as predictors of metabolic risk. Recently, the sulfur-containing amino acids (SAA) methionine and cysteine have been suggested to play roles in development of obesity and related metabolic disease. In animals, dietary restriction of SAA increases insulin sensitivity and reduces adiposity. Research in STAY comprises human interventional and epidemiologic studies to establish the role of dietary, circulating and urinary sulfur amino acids and related compounds as modifiable risk factors in human metabolic health and obesity. We will perform a dietary intervention study in participants with overweight and obesity to evaluate effects of a SAA restricted plant-based diet on body fatness and energy balance, as well as biomarkers and gene expression patterns related to energy metabolism. In addition, we will use data from a large Dutch cohort to investigate whether dietary patterns are associated with SAA in plasma and urine, and with body fat, morbidity and mortality. Genetic data from this cohort will be used to investigate gene-nutrient interactions. The project will use state-of-the-art methodology to assess plasma and urine amino acids, plasma lipids and fatty acid profiles, glucose tolerance, adipokines and appetite-related hormones. Overall, the project can potentially translate the well-described beneficial findings of dietary SAA restriction in animals to humans with obesity. Research in STAY will provide unique insight into the SAA-mediated regulation of energy metabolism, appetite, obesity and metabolic disease. Because an SAA restricted diet is largely plant-based, the STAY project will enhance understanding of the mechanisms by which a plant-based diet low in SAA content can benefit human metabolic health.