Metabolomics: A Promising Tool to Improve the Understanding of the Developmental Origins of Obesity and Metabolic Disease.
LaBarre, Jennifer
2019
Abstract
The prevalence of obesity and type 2 diabetes continues to rise in the pediatric and adult population. This increase in metabolic disease may be partially due to programming during sensitive periods of development. Metabolomics is a powerful tool to identify molecular biomarkers and mechanistic insights into adverse health outcomes. This dissertation describes the use of metabolomic profiling to define the metabolic environment in two human cohorts, during gestation and the pubertal transition, and relate them mechanistically to growth and metabolism outcomes. Lipidomic profiles performed on first trimester maternal plasma (M1), delivery maternal plasma (M3), and infant umbilical cord plasma (CB) in 106 mother-infant dyads showed selective transport of long-chain polyunsaturated fatty acids (PUFA) as well as lysophosphatidylcholine (LysoPC) and lysophosphatidylethanolamine (LysoPE) into CB. Using linear models, CB LysoPC and LysoPE groups were positively associated with birth weight, a commonly assessed indicator of gestational implications on fetal growth. M1 PUFA containing triglycerides and phospholipids appear to modulate the levels of the CB lysophospholipids related to BW. Furthermore, epigenome-wide DNA methylation was measured in CB leukocytes to determine how the maternal lipidome across gestation may influence fetal programming. M3 saturated LysoPCs and LysoPEs were associated with differential methylation in CpG islands within genes pertaining to cell proliferation and growth. These results highlight the influence of the maternal lipidome on the infant epigenome. A growing body of evidence suggests a relationship between the metabolome and metabolic health in adults, however, less is known in children and adolescents in the pubertal transition, who have changing hormonal patterns and accumulation of muscle and fat tissue. Using untargeted metabolomics, metabolites associated with BMI z-score include positive associations with diglycerides among girls and positive associations with branched chain and aromatic amino acids in boys. In contrast to that found in adults, medium-chain acylcarnitines were inversely associated with insulin resistance (IR), suggesting less imbalance in the delivery and oxidation of substrates in adolescents, perhaps due to the increased substrate utilization to fuel tissue and linear growth. Path analysis identified metabolites that underlie the relationship between energy-adjusted macronutrient intake with IR. Carbohydrate intake is positively associated with IR through decreases in intermediates of β-oxidation, while fat intake is positively associated with IR through increases in extra-mitochondrial fatty acid metabolism, the latter identified by accumulation of dicarboxylic fatty acids. Thus, biomarkers of IR and mitochondrial oxidative capacity may depend on the relative nutrient mix and an individual’s intrinsic mitochondrial metabolism. These studies demonstrate the ability to generate inferential hypotheses about metabolism by acquiring high dimensional metabolomics data. The suggested modulation of uptake of lysophospholipids into the developing fetus, potentially influencing birth weight, by PUFAs exposure in the first trimester could be tested in larger cohorts or experimentally by timed PUFA intake. Longitudinal follow-up is needed to identify if fetal programming, via the establishment of DNA methylation patterns at birth, influences risk of adult metabolic disease. During adolescence, our findings confirm and extend associations between the metabolome with obesity and IR, emphasizing sex-specific differences due to variations in muscle and fat tissue accumulation in puberty. These results suggest that adolescents prone to IR have an increase in selection of carbohydrates for fuel, exacerbated by elevated habitual carbohydrate consumption. Using controlled feeding studies, intrinsic differences in mitochondrial metabolism and the consequence of habitual macronutrient intake on IR could be directly tested.Subjects
metabolomics developmental origins of health and disease human cohort bioinformatics
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