The prevalence of overweight and obesity are increasing worldwide. The World Health Organization reports that 1.9 billion people were overweight and 650 million were obese in 2016. Many people are aware that obesity leads to increased risk of chronic diseases and mortality, yet struggle to lose weight and maintain weight loss.

Research over the last decade suggests that methionine and cysteine, two dietary amino acids that are abundant in proteins from animal sources, play a role in development of obesity and related metabolic diseases. In mice and rats, diets low in methionine and cysteine content were found to improve glucose and lipid metabolism and reduce body fat. In human studies in thousands of subjects, blood levels of cysteine were found to be higher in overweight and obese individuals, in a dose-dependent manner. In the STAY project, we aim to examine whether we can achieve the beneficial findings seen in animal experiments in humans with obesity.

We have performed a randomized controlled dietary intervention 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) and gene expression patterns. The trial protocol was published in Journal of Translational Medicine (IF 8.44). A total of 61 participants were randomized to the intervention, and the data collection was completed March 2022. In addition to the trial, we analyze data form a large Dutch population study to investigate associations of dietary, circulating and urinary methionine and cysteine with body fat and chronic disease, including diabetes. Using genetic data from this population, we investigate if genetic variation in genes that are involved in SAA metabolism are linked to the effect of diet on body fatness. In the analytical part of the STAY project, we have used state-of-the-art methodology to assess plasma and urine sulfur amino acids and related compounds, plasma lipid and fatty acid profiles, glucose tolerance, and obesity and appetite-related hormones to increase our understanding of how methionine and cysteine are linked to increased body adiposity.

Statistical analyses on data from both the intervention trial and the Dutch population study are ongoing. Results from the trial indicate effects on body weight and on several biomarkers in plasma and urine (manuscript submitted December 2022). The first article from the cohort study was published in November 2022 on the associations of plasma concentrations of methionine and cysteine with different fat depots(doi: 10.1007/s00394-022-03041-4). The second paper from the cohort on the dietary determinants of circulating sulfur amino acids was submitted in December 2022.

In combination, this project will help us understand the role of methionine and cysteine in human obesity and obesity related diseases, and to what extent their restriction by a plant-based diet can facilitate weight loss and improve metabolic health.

In STAY we have in 2022 published two original papers and held several presentations at exernal meetings and conferences. 

Published papers in 2022:

Tore EC, Elshorbagy AK, Bakers FCH et al. Associations between plasma sulfur amino acids and specific fat depots in two independent cohorts: CODAM and The Maastricht Study. Eur J Nutr. 2022 Nov 2. https://doi.org/10.1007/s00394-022-03041-4. Brief summary: The relations between plasma sulfur amino acids and adiposity were investigated in two Dutch populations enriched with individuals with prediabetes and type 2 diabetes. Main findings were that plasma methionine was positively associated with measures of liver fat, whereas plasma total cysteine was associated with greater general, central and peripheral adiposity.

Nichenametla SN, Mattocks DAL, Cooke D, Midya V, Malloy VL, Mansilla W, Øvrebø B, Turner C, Bastani NE, Sokolová J, Pavlíková M, Richie JP Jr, Shoveller AK, Refsum H, Olsen T, Vinknes KJ, Kožich V, Ables GP. Cysteine restriction-specific effects of sulfur amino acid restriction on lipid metabolism. Aging Cell. 2022 Dec;21(12):e13739. https://doi.org/10.1111/acel.13739.  Epub 2022 Nov 19. Brief summary:  Using methionine- and cysteine-titrated diets in rodent models, this study demonstrates that methionine restriction and cysteine restriction exert discrete biological effects. For example, the anti-adiposity effects of sulfur amino acids restriction are due to cysteine restriction. Furthermore, data indicate that cysteine restriction increases serinogenesis (serine biosynthesis from non-glucose substrates). The translational relevance of the preclinical data where investigated in humans: there were negative and positive correlations of plasma serine and cysteine, respectively, with triglycerides and metabolic syndrome criteria in a cross-sectional epidemiological study. In an intervention trial with a diet in low-sulfur amino acid and high-polyunsaturated fatty acid, plasma serine increased.