All ETDs from UAB

Advisory Committee Chair

William Timothy Garvey

Advisory Committee Members

Daniel Larry Smith

Gang Liu

Pi-Ling Chang

Yuchang Fu

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) School of Health Professions

Abstract

This research sought to identify the effects of prenatal and postnatal factors on systemic metabolism and the regulation of food intake, weight, and body composition. It was found that the manipulation of maternal diets influenced the systemic metabolism of offspring. The offspring of dams fed an isocaloric, low protein diet were significantly smaller and consumed less food than offspring from dams fed a control diet. In the case of the offspring from dams fed a western diet, they were significantly heavier and consumed more food than offspring from dams fed a control diet. In addition, the offspring showed altered glucose tolerance and insulin resistance as a function of maternal diets, and effects were observed throughout growth, development, and in response to the modulatory effects of aging and their post-weaning diet. The offspring showed different insulin and leptin concentrations depending on maternal diets, and the altered levels may partially explain differences among groups. Our data indicates that in utero environmental factors program offspring’s metabolism into adulthood, and can contribute to the intergenerational transmission of obesity and cardiometabolic diseases. We hypothesized that DNA methylation occurring prenatally were responsible for altered expression of micro-RNAs (miRNAs), known regulators of gene expression. The absence of miR-150 resulted in increased mTOR protein known to participate in increased leptin production, which leads to reduction of food intake. miR-150 KO mice were found to have an insulin-sensitive phenotype accompanied by changes of gene and protein expression in adipose tissue. Ablation of miR-150 also augmented PGC-1α protein, which subsequently led to expression of genes involved in a futile cycle between fatty acid oxidation and triglyceride synthesis in adipose tissue. However, we found that there was no difference in miR-150 concentration among newborn offspring from dams fed different diets. In summary, we found that the maternal diets and miR-150 are important contributors to regulating systemic metabolism before and after birth, respectively. This data points to potential environmental factors that could be modified during pregnancy to prevent the intergenerational transmission of cardiometabolic disease, and a novel therapeutic target to treat metabolic disease once it is observed in adulthood.

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