Lifestyle, branched-chain amino acids, and cardiovascular risk factors: a randomized trial

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Abstract Cardiovascular diseases (CVD) are the primary cause of premature death worldwide, and risk factors such as insulin resistance and type 2 diabetes are increasing in prevalence. Therefore, more effective preventive interventions to improve cardiometabolic health are urgently needed. Circulating branched-chain amino acids (BCAA) are strong predictors of type 2 diabetes and CVD. Furthermore, experimental and genetic studies indicate that BCAA overload has adverse cardiometabolic effects. Thus, BCAA levels may be novel targets for preventive interventions. In addition, BCAA levels of individuals may inform personalized interventions. Evidence is accumulating that diet composition, physical activity, and weight loss can reduce plasma BCAA levels by affecting the dietary supply, gut microbiota production, or catabolism of BCAA. However, evidence on the impact of lifestyle factors on BCAA levels is mainly based on small experimental studies and cross- sectional studies. Larger trials and longitudinal studies are crucial to determine whether lifestyle exposures can substantially affect BCAA levels. Furthermore, research on the health consequences of BCAA levels has focused chiefly on the impact of BCAA levels on glucose metabolism, but adverse effects on other CVD risk factors such as inflammation, blood pressure, and dyslipidemia are plausible. The PREMIER study is a randomized trial of the impact of behavioral lifestyle interventions on CVD risk factors with detailed information on diet and physical activity based on interviews and biological measurements. We will measure serum BCAA and other metabolites using targeted quantitative NMR metabolomics in serum samples of 729 participants at baseline and after six months of lifestyle interventions. Our specific aims are as follows: 1). To assess the impact of the randomized lifestyle interventions on circulating BCAA levels over six months. We will evaluate the effect of the ‘established lifestyle intervention,’ including weight loss and increases in physical activity, and the effect of the intervention with added counseling to improve dietary patterns as compared with the control arm. 2). To evaluate specific dietary factors, physical activity, and changes in adiposity in relation to BCAA changes. We will examine changes in physical activity, fitness, protein and BCAA intakes, and healthy plant-based dietary patterns. 3). To evaluate whether changes in BCAA levels affect cardio-metabolic risk factors, including blood lipid profiles, blood pressure, and markers of inflammation and insulin sensitivity. We will also estimate the proportion of the effects of lifestyle changes on cardiovascular risk factors explained by reductions in BCAA levels. Our findings may inform dietary and lifestyle recommendations that consider the impact on BCAA levels.