Stearoyl-CoA desaturase and energy metabolism in humans

According to estimates by the World Health Organization, 1.9 billion people were overweight and 650 million were obese in 2016. Overweight and obesity increase the risk of a number of chronic conditions like hypertension, diabetes type 2, dyslipidemia, stroke, heart disease, and some types of cancers. Achieving and maintaining energy balance and thereby prevention of obesity is a major issue in relation to health worldwide. In obesity management, small positive energy imbalances are a natural target for intervention, and dietary behaviour such as the type of fat and protein consumed may contribute to weight control. Stearoyl-coenzyme A desaturase 1 (SCD1) is a key enzyme in fatty acid metabolism associated with the degree of obesity in rodents and humans. An increasing number of studies suggest that polyunsaturated fatty acids and the sulphur-containing amino acids methionine (Met) and cysteine (Cys) are involved in the regulation of SCD1 activity and fat mass. Further, dietary restriction of Met-Cys has proved to be beneficial for weight reduction and disease prevention in animal studies. Through randomized dietary pilot studies, we investigated the effects of diets with different content of polyunsaturated fatty acids and/or Met-Cys on metabolic markers, including glucose, insulin and lipids, concentrations of plasma and urine sulphur amino acids, plasma fatty acids and SCD activity indices, and adipose tissue gene expression. In the first pilot study, normal weight volunteers were recruited to consume a diet rich in polyunsaturated fatty acids and low in Met-Cys or a diet rich in saturated fatty acids and Met-Cys. The study consisted of two intervention phases (test meal and 7-day intervention) in healthy free-living men and women (n = 10-14, 20-40 y). We primarily examined the effects of a single test meal and a 7-day intervention on plasma and urinary concentrations of sulphur amino acids. The study demonstrated acute changes in several of the plasma amino acids including Met and Cys following intake of a single test meal low in Met-Cys. Similarly, we observed changes in several sulphur amino acids, including Met in the low Met-Cys group compared with the high Met-Cys group after 7-days of intervention. Cys in urine, but not plasma was significantly reduced in the low Met-Cys group after 7-days. We did not observe an effect of the diets on plasma SCD activity indices. Based on the results from the first pilot study we conducted another pilot study with focus on restriction of Met-Cys among women with overweigh or obesity (n = 20, 20-40 y). The participants were randomized to receive a diet with either low, moderate of high content of Met-Cys for 7-days. In addition, we examined gene expressions in adipose tissue. After 7-days of intervention we observed a tendency towards improvements in plasma markers of lipids and glucose metabolism. In addition, there were changes in plasma and urinary concentrations of several of the sulphur amino acids and in adipose tissue mRNA expression in the low Met-Cys group compared with the high Met-Cys group, as well as reductions in plasma SCD1 activity index. In this project, we have demonstrated acceptable feasibility and tolerance of a Met-Cys restricted diet, in addition identified relevant biomarkers related to energy metabolism and obesity development that may be regulated by such a diet. The results from these pilot studies are important for designing future, long-term dietary intervention studies that can examine whether restriction of Met-Cys is beneficial for body composition and weight control in individuals with overweigh and obesity.

The project results will aid in the design and implementation of future large-scale dietary interventions into whether dietary methionine and cysteine restriction can confer sustainable and beneficial effects over time in individuals with overweight or obesity. The project has already laid the foundation for and initiated an International Collaborative EU Project in JPI HDL (NFR grant no: ES653434) that will proceed with intervention studies in humans to establish whether dietary sulphur amino acid restriction can improve body weight, body composition and energy expenditure. This may enhance understanding of the mechanisms by which lowering dietary sulphur amino acid content can benefit metabolic health in humans and potential aid in prevention and treatment of obesity and co-morbidities.

BACKGROUND: Obesity is a major public health problem related to enhanced risk of cardiovascular disease, type 2 diabetes, cancer, and overall mortality. Stearoyl-coenzyme A desaturase (SCD) is a key enzyme in fatty acid and energy metabolism with the specific function of desaturating saturated fatty acids. In rodents as well as humans, high SCD1 activity is considered to be involved in development of obesity. In animal models, polyunsaturated fatty acids (PUFA) inhibit Scd1 gene expression and at the population level, dietary PUFA and plasma PUFA show strong inverse associations with plasma SCD indices. Emerging evidence also suggests a role for the sulphur amino acid cysteine in regulating SCD1 activity and obesity. AIM: To examine if changing SCD1 activity through dietary interventions can increase energy metabolism in humans. METHOD AND STUDY POPULATION: Through short-term randomized intervention trials, we will recruit free-living, healthy normal-weight and obese subjects to consume a diet rich in PUFA and low in cysteine or a diet rich in saturated fatty acids and cysteine. Blood and biopsy samples will be taken from subjects for measurements of biomarkers at baseline and post intervention. The following projects are planned: a) Document changes in plasma SCD indices, lipids, fatty acids, amino acids, insulin, glucose, inflammation and satiety markers b) Examine the effects of the diets on body composition, energy expenditure, mRNA expression, protein and metabolite levels in relation to lipid and glucose metabolism c) Investigate effects of the interventions on hunger, appetite, and satiety patterns. IMPLICATIONS: Dietary regulation of SCD1 activity may be beneficial for achieving a normal energy balance. The results will be important for defining the impact of PUFA and cysteine on relevant biomarkers in relation to lipid and energy metabolism.