Abstract
Stress is one of the most critical determinants of lifetime health and increases the risk of chronic non-communicable diseases. To gain insight into underlying environment-gene interactions, we analyzed the cardiorenal metabolome of adult mice exposed to multidimensional early-life transportation stress. Using proton nuclear magnetic resonance (1H NMR) spectroscopy, we show that early life stress permanently programs metabolic pathways in somatic organs linked to cardiorenal and mental health disorders in later life. Heart and kidneys of stressed mice revealed robust metabolic markers linked to abnormal energy metabolism, branched-chain amino acid biosynthesis and degradation, methylhistidine metabolism, arginine and proline metabolism, glycine and serine metabolism, and aminoacyl-tRNA biosynthesis. These markers were strongly associated with anxiety-like behaviours. Dysregulation of energy and protein metabolism suggests an increased risk of metabolic diseases like insulin resistance, cardiorenal syndrome, diabetes, and obesity. These findings provide novel insights into the direct effects of early life stress on cardiorenal metabolism and are consistent with prior observations of increased non-communicable disease risk in stressed populations. Thus, stress-associated metabolic signatures in somatic organs may provide early predictors of health risks in later life and reveal new candidates for peripheral biomarker detection with diagnostic value.
Highlights
Stress is one of the most critical determinants of lifetime health and increases the risk of chronic noncommunicable diseases
We found that multidimensional early life stress was linked to chronic cardiorenal metabolic pathologies in adulthood based on stressed animals having altered (i) organ weights, (ii) affective state, and (iii) metabolites and/or metabolic pathways linked to adverse mental health outcomes and metabolic illness, such as cardiorenal syndrome, insulin resistance, diabetes, and obesity
Experience-dependent metabolic markers in heart and kidney are involved in energy metabolism, branched-chain amino acid biosynthesis and degradation, methylhistidine metabolism, arginine and proline metabolism, and glycine and serine metabolism
Summary
Stress is one of the most critical determinants of lifetime health and increases the risk of chronic noncommunicable diseases. Using proton nuclear magnetic resonance (1H NMR) spectroscopy, we show that early life stress permanently programs metabolic pathways in somatic organs linked to cardiorenal and mental health disorders in later life. Heart and kidneys of stressed mice revealed robust metabolic markers linked to abnormal energy metabolism, branched-chain amino acid biosynthesis and degradation, methylhistidine metabolism, arginine and proline metabolism, glycine and serine metabolism, and aminoacyl-tRNA biosynthesis These markers were strongly associated with anxiety-like behaviours. Dysregulation of energy and protein metabolism suggests an increased risk of metabolic diseases like insulin resistance, cardiorenal syndrome, diabetes, and obesity. Traditional risk factors for chronic diseases such as poor nutrition, inactivity, and adiposity do not fully account for the excess burden of NCDs in the population Other factors such as stress may be precipitating events in the development and progression of chronic non-communicable conditions. We identified clearly distinguishable cardiorenal metabolic signatures and mechanistic pathways linking impaired cardiorenal function to mental health disorders
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