Dietary sulfur amino acid restriction in humans with overweight and obesity: Evidence of an altered plasma and urine sulfurome, and a novel metabolic signature that correlates with loss of fat mass and adipose tissue gene expression
Thomas Olsen,
Kathrine J. Vinknes,
Kristýna Barvíková,
Emma Stolt,
Sindre Lee-Ødegård,
Hannibal Troensegaard,
Hanna Johannessen,
Amany Elshorbagy,
Jitka Sokolová,
Jakub Krijt,
Michaela Křížková,
Tamás Ditrói,
Péter Nagy,
Bente Øvrebø,
Helga Refsum,
Magne Thoresen,
Kjetil Retterstøl,
Viktor Kožich
Affiliations
Thomas Olsen
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine University of Oslo, Postboks 1046 Blindern, 0317 Oslo, Norway; Corresponding author.
Kathrine J. Vinknes
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine University of Oslo, Postboks 1046 Blindern, 0317 Oslo, Norway
Kristýna Barvíková
Department of Pediatrics and Inherited Metabolic Disorders, Charles University, First Faculty of Medicine, and General University Hospital, Ke Karlovu 2, 128 00 Prague, Czech Republic
Emma Stolt
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine University of Oslo, Postboks 1046 Blindern, 0317 Oslo, Norway
Sindre Lee-Ødegård
Department of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Postboks 4959 Nydalen, OUS HF Aker sykehus, 0424 Oslo, Norway
Hannibal Troensegaard
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine University of Oslo, Postboks 1046 Blindern, 0317 Oslo, Norway
Hanna Johannessen
Department of Pathology, Oslo University Hospital, Rikshospitalet, Postboks 45980 Nydalen, OUS HF Rikshospitalet, 0424 Oslo, Norway
Amany Elshorbagy
Department of Physiology, Faculty of Medicine, University of Alexandria, Chamblion street, Qesm Al Attarin, Alexandria 5372066, Egypt; Department of Pharmacology, University of Oxford, Mansfield Rd, Oxford OX1 3QT, UK
Jitka Sokolová
Department of Pediatrics and Inherited Metabolic Disorders, Charles University, First Faculty of Medicine, and General University Hospital, Ke Karlovu 2, 128 00 Prague, Czech Republic
Jakub Krijt
Department of Pediatrics and Inherited Metabolic Disorders, Charles University, First Faculty of Medicine, and General University Hospital, Ke Karlovu 2, 128 00 Prague, Czech Republic
Michaela Křížková
Department of Pediatrics and Inherited Metabolic Disorders, Charles University, First Faculty of Medicine, and General University Hospital, Ke Karlovu 2, 128 00 Prague, Czech Republic
Tamás Ditrói
Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Ráth György u. 7-9, 1122 Budapest, Hungary
Péter Nagy
Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Ráth György u. 7-9, 1122 Budapest, Hungary; Department of Anatomy and Histology, HUN-REN–UVMB Laboratory of Redox Biology Research Group, University of Veterinary Medicine, 1078 Budapest, Hungary; Chemistry Institute, University of Debrecen, 4012 Debrecen, Hungary
Bente Øvrebø
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine University of Oslo, Postboks 1046 Blindern, 0317 Oslo, Norway; Department of Food Safety, Norwegian Institute of Public Health, Postboks 222 Skøyen, 0213 Oslo, Norway
Helga Refsum
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine University of Oslo, Postboks 1046 Blindern, 0317 Oslo, Norway; Department of Pharmacology, University of Oxford, Mansfield Rd, Oxford OX1 3QT, UK
Magne Thoresen
Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Postboks 1122 Blindern, 0317 Oslo, Norway
Kjetil Retterstøl
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine University of Oslo, Postboks 1046 Blindern, 0317 Oslo, Norway; The Lipid Clinic, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Postboks 4959 Nydalen, OUS HF Aker sykehus, 0424 Oslo, Norway
Viktor Kožich
Department of Pediatrics and Inherited Metabolic Disorders, Charles University, First Faculty of Medicine, and General University Hospital, Ke Karlovu 2, 128 00 Prague, Czech Republic; Corresponding author.
Background: In animals, dietary sulfur amino acid restriction (SAAR) improves metabolic health, possibly mediated by altering sulfur amino acid metabolism and enhanced anti-obesogenic processes in adipose tissue. Aim: To assess the effects of SAAR over time on the plasma and urine SAA-related metabolites (sulfurome) in humans with overweight and obesity, and explore whether such changes were associated with body weight, body fat and adipose tissue gene expression. Methods: Fifty-nine subjects were randomly allocated to SAAR (∼2 g SAA, n = 31) or a control diet (∼5.6 g SAA, n = 28) consisting of plant-based whole-foods and supplemented with capsules to titrate contents of SAA. Sulfurome metabolites in plasma and urine at baseline, 4 and 8 weeks were measured using HPLC and LC-MS/MS. mRNA-sequencing of subcutaneous white adipose tissue (scWAT) was performed to assess changes in gene expression. Data were analyzed with mixed model regression. Principal component analyses (PCA) were performed on the sulfurome data to identify potential signatures characterizing the response to SAAR. Results: SAAR led to marked decrease of the main urinary excretion product sulfate (p < 0.001) and plasma and/or 24-h urine concentrations of cystathionine, sulfite, thiosulfate, H2S, hypotaurine and taurine. PCA revealed a distinct metabolic signature related to decreased transsulfuration and H2S catabolism that predicted greater weight loss and android fat mass loss in SAAR vs. controls (all pinteraction < 0.05). This signature correlated positively with scWAT expression of genes in the tricarboxylic acid cycle, electron transport and β-oxidation (FDR = 0.02). Conclusion: SAAR leads to distinct alterations of the plasma and urine sulfurome in humans, and predicted increased loss of weight and android fat mass, and adipose tissue lipolytic gene expression in scWAT. Our data suggest that SAA are linked to obesogenic processes and that SAAR may be useful for obesity and related disorders. Trial identifier: https://clinicaltrials.gov/study/NCT04701346.
