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Abstract
BackgroundDietary 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 effects of dietary methionine and cysteine restriction on cardiometabolic risk factors, plasma and urinary amino acid profile, serum fibroblast growth factor 21 (FGF21), and subcutaneous adipose tissue gene expression in women with overweight and obesity in a double-blind randomized controlled pilot study.MethodsTwenty women with overweight or obesity were allocated to a diet low (Met/Cys-low, n = 7), medium (Met/Cys-medium, n = 7) or high (Met/Cys-high, n = 6) in methionine and cysteine for 7 days. The diets differed only by methionine 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.ResultsPlasma 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.ConclusionsOur data suggest that dietary methionine and cysteine restriction may have beneficial effects on circulating biomarkers, including FGF21, and influence 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.Trial registration ClinicalTrials.gov Identifier: NCT03629392, registration date: 14/08/2018 https://clinicaltrials.gov/ct2/show/NCT03629392.
Highlights
Dietary restriction of methionine and cysteine is a well-described model that improves metabolic health in rodents
Statistical analysis Null-hypothesis testing is actively discouraged in pilot trials, because we have screened a wide range of potential outcomes with relevance for a future largescale study, we have reported p-values and confidence intervals (CI), but stress that these estimates should be interpreted with care as per the CONSORT statement for reporting of clinical trials and pilot trials [25, 26]
When we excluded the subject with high homeostatic model of insulin resistance (HOMA-IR) at baseline, results tended towards a greater reduction in the Met/Cys-low compared to the Met/Cys-high group was observed (− 15.4%, − 30.4–3.0%). This double-blind randomized controlled pilot study describes for the first time the effects of dietary restriction of both methionine and cysteine content, with either severe or moderate restriction on plasma biomarkers and subcutaneous adipose tissue mRNA expression related to energy metabolism, in healthy overweight and obese women
Summary
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 effects of dietary methio‐ nine and cysteine restriction on cardiometabolic risk factors, plasma and urinary amino acid profile, serum fibroblast growth factor 21 (FGF21), and subcutaneous adipose tissue gene expression in women with overweight and obesity in a double-blind randomized controlled pilot study. Plasma methionine and total cysteine (tCys) are associated with body mass index (BMI), fat mass, insulin resistance and markers of the activity of the lipogenic enzyme stearoyl coenzyme A desaturase (SCD) [8,9,10,11]. Dietary restriction of methionine and cysteine are associated with several beneficial metabolic effects including increased energy expenditure, enhanced insulin sensitivity and decreased adiposity [12,13,14,15]. The available literature from preclinical work support that fibroblast growth factor 21 (FGF21), a member of the endocrine FGF superfamily, is one of the main factors that regulate lipid and glucose metabolism in methionine restricted mice [18,19,20]
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