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Effects of Dietary Methionine and Cysteine Restriction on Plasma Biomarkers, Serum Fibroblast Growth Factor 21, and Adipose Tiss

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Effects of Dietary Methionine and Cysteine Restriction on Plasma Biomarkers, Serum Fibroblast Growth Factor 21, and Adipose Tiss Olsen et al. J Transl Med (2020) 18:122 https://doi.org/10.1186/s12967-020-02288-x Journal of Translational Medicine RESEARCH Open Access Efects of dietary methionine and cysteine restriction on plasma biomarkers, serum fbroblast growth factor 21, and adipose tissue gene expression in women with overweight or obesity: a double-blind randomized controlled pilot study Thomas Olsen1*, Bente Øvrebø1, Nadia Haj‑Yasein1, Sindre Lee1, Karianne Svendsen1,2, Marit Hjorth1, Nasser E. Bastani1, Frode Norheim1, Christian A. Drevon1, Helga Refsum1 and Kathrine J. Vinknes1 Abstract Background: Dietary restriction of methionine and cysteine is a well‑described model that improves metabolic health in rodents. To investigate the translational potential in humans, we evaluated the efects of dietary methio‑ nine and cysteine restriction on cardiometabolic risk factors, plasma and urinary amino acid profle, serum fbroblast growth factor 21 (FGF21), and subcutaneous adipose tissue gene expression in women with overweight and obesity in a double‑blind randomized controlled pilot study. Methods: Twenty women with overweight or obesity were allocated to a diet low (Met/Cys n 7), medium (Met/ ‑low, = Cys‑medium, n 7) or high (Met/Cys‑high, n 6) in methionine and cysteine for 7 days. The diets difered only by methio‑ nine and cysteine= content. Blood and urine= were collected at day 0, 1, 3 and 7 and subcutaneous adipose tissue biopsies were taken at day 0 and 7. Results: Plasma methionine and cystathionine and urinary total cysteine decreased, whereas FGF21 increased in the Met/Cys‑low vs. Met/Cys‑high group. The Met/Cys‑low group had increased mRNA expression of lipogenic genes in adipose tissue including DGAT1. When we excluded one participant with high fasting insulin at baseline, the Met/ Cys‑low group showed increased expression of ACAC, DGAT1, and tendencies for increased expression of FASN and SCD1 compared to the Met/Cys‑high group. The participants reported satisfactory compliance and that the diets were moderately easy to follow. Conclusions: Our data suggest that dietary methionine and cysteine restriction may have benefcial efects on circu‑ lating biomarkers, including FGF21, and infuence subcutaneous adipose tissue gene expression. These results will aid in the design and implementation of future large‑scale dietary interventions with methionine and cysteine restriction. *Correspondence: [email protected] 1 Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Postboks 1046, Blindern, 0317 Oslo, Norway Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Olsen et al. J Transl Med (2020) 18:122 Page 2 of 15 Trial registration ClinicalTrials.gov Identifer: NCT03629392, registration date: 14/08/2018 https ://clini caltr ials.gov/ct2/ show/NCT03 62939 2. Keywords: Methionine restriction, Dietary intervention, Plasma biomarkers, Translational research, Adipose tissue, mRNA expression Background indicated by reversal of the benefcial efects of methio- Overweight and obesity are major risk factors for meta- nine restriction by cysteine supplementation [13]. To our bolic disruptions including dyslipidemia and insulin knowledge, no studies have focused on efects of com- resistance that increase overall risk of morbidity and bined methionine and cysteine restriction in overweight mortality [1, 2]. Dietary intervention is a common strat- and obese populations. Furthermore, no studies have egy in obesity management; however, whether specifc evaluated whether moderate reduction (~ 35% relative dietary interventions are more efcient than others for to controls), may have similar metabolic efects and be a weight control is still debated. Dietary restriction of the more feasible approach both in research settings as well sulfur amino acids methionine and cysteine has the past as in everyday life. decades become increasingly recognized as a research Te primary aim of this pilot study was to evaluate the model to promote leanness and longevity in animals potential efects of a 7-day diet low, moderate or high in [3–6]. methionine and cysteine content on a wide selection of Methionine is an essential amino acid that through a potential outcomes identifed in preclinical and observa- sequence of reactions can be converted to cysteine [7]. tional studies [9, 13, 14, 16, 18] that may aid in the plan- Cysteine is a precursor of the antioxidant glutathione, ning and design of a future large-scale study. Outcome and taurine via catabolism by the enzyme cysteine dioxy- measures included plasma lipids, amino acids, glucose, genase (CDO). In human observational studies, plasma serum FGF21, and other biomarkers related to energy methionine and total cysteine (tCys) are associated with metabolism, including adipose tissue gene expression body mass index (BMI), fat mass, insulin resistance and and plasma SCD activity indices in healthy women with markers of the activity of the lipogenic enzyme stearoyl overweight and obesity. coenzyme A desaturase (SCD) [8–11]. In rodents, die- tary restriction of methionine and cysteine are associ- ated with several benefcial metabolic efects including Materials and methods increased energy expenditure, enhanced insulin sensitiv- Study design ity and decreased adiposity [12–15]. One of the primary We conducted a 7-day, double-blind, randomized con- biological responses includes efects on lipid metabolism trolled pilot intervention study at the Centre for Clini- such as increased expression of genes involved in de novo cal Nutrition at Institute of Basic Medical Sciences, lipogenesis, lipolysis and fatty acid oxidation in liver and University of Oslo, Norway from October 2018 until white adipose tissue [13, 16, 17]. Te available literature February 2019. Te participants were recruited through from preclinical work support that fbroblast growth fac- the social media channels of the Faculty of Medicine tor 21 (FGF21), a member of the endocrine FGF super- and the Department of Nutrition, University of Oslo. family, is one of the main factors that regulate lipid Of the 195 participants that were assessed for eligibility, and glucose metabolism in methionine restricted mice 20 were randomly assigned, and 19 completed all study [18–20]. visits (Fig. 1). Te participants were healthy women Despite the clear benefts of methionine and cysteine with overweight or obesity (BMI 25–35 kg/m2) aged restriction in animal experiments, and epidemiologic 20–40 years. Participants were also included if body fat data suggesting that cysteine is obesogenic [21], there percentage corresponded to > 33% as measured by dual- are few controlled dietary interventions with methionine energy X-ray absorptiometry [23]. Exclusion criteria and cysteine restriction in humans. One dietary interven- were presence of major chronic disease, use of medica- tion with severe restriction of methionine (> 80% relative tions, smoking, strenuous physical activity ≥ 3 times/ to controls), but not cysteine, in subjects with metabolic week, veganism, pregnancy, and breastfeeding. Because syndrome (n = 26), demonstrated increased fat oxida- this was a pilot study where we did not have sufcient tion compared to the control group, whereas there were information on relevant efects from previous stud- no diferences in cardiometabolic risk markers and body ies, no formal power calculations were performed. Te composition [22]. Te lack of efects in the intervention number of participants were based on expected partici- group in this study might be due to cysteine intakes as pant recruitment applying the same strategies as in our Olsen et al. J Transl Med (2020) 18:122 Page 3 of 15 were recommended to avoid strenuous physical activity, to abstain from alcohol and fast 10 h before blood sampling. All participants gave written informed consent. Te study was conducted according to the guidelines in the Declaration of Helsinki, and the Regional Ethics Com- mittee for Medical Research in South East Norway approved the study (reference number: 2015/634). Te study was registered at US National Library of Medi- cine Clinical Trials registry (ClinicalTrials.gov Identifer: NCT03629392, registration date: 14/08/2018). Dietary interventions Te diet was based on the intervention in a previous pilot study [24] with some modifcations. Te diet was adjusted to the Nordic Nutrient Recommendations for females aged 18–60 years with an average energy require- ment corresponding to about 2200 kcal/d [27]. Because the main aim of the study was to compare diets contrast- ing in sulfur amino acid content, the total number of calories were the same for each participant. A detailed overview of the nutrient composition of the diet is pre- sented in Additional fle 1. Meals were developed to ft a Norwegian cuisine and available ingredients. A typical Fig. 1 Flow chart of the study participants and progression. The menu is displayed in Additional fle 2. Met/Cys groups had low, medium or high intake of methionine and Sulfur amino acids are found in most foods but are cysteine. 1One participant did not complete the last visit (V4), but all especially high in animal products.
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