Doctor of Philosophy (PhD)
The twenty-first century has experienced a shift in cause of death worldwide from communicable diseases to noncommunicable diseases. Interestingly, many of these implicated chronic diseases, such as cancer, diabetes, and cardiovascular disease, have been shown to be programmed in the womb. As first posited by the Barker Hypothesis, adverse exposures in utero can increase an individual’s risk for chronic disease later in life. Therefore, pregnancy is an opportune time for intervention to improve the health of future generations. Studies of exposures known to negatively impact infant health, e.g. states of overnutrition (obesity, diabetes, excess gestational weight gain) and undernutrition (starvation, protein restriction), are critical to reveal the mechanisms of and identify markers for developmental programming. Numerous endocrine signals including insulin, leptin, and adiponectin have been extensively investigated during pregnancy with aberrant effects on offspring growth and metabolic function. A novel endocrine hormone, fibroblast growth factor 21 (FGF21), which has been recently implicated as a signal for protein restriction, has not yet been studied for a potential role in developmental programming of future disease. Therefore, we aimed to investigate the role of FGF21 in pregnancy. We hypothesized FGF21 may be a nutrient sensor and a signal for fetal nutrient insufficiency during pregnancy. In studies of healthy, pregnant women, we found FGF21 was acutely regulated by maternal macronutrient balance. We then found in both mice and human studies that FGF21 is elevated in response to low maternal protein intake in pregnancy. We also showed elevated maternal FGF21 correlated with decreased infant size in the first year of life, an outcome commonly associated with reduced maternal protein intake in pregnancy. Finally, we used the Protein Leverage Hypothesis to directly test whether FGF21 is indeed a protein sensor in pregnancy and found that FGF21 is required for the hyperphagic response to low protein intake in pregnancy. In summary, these studies support the hypothesis that FGF21 is a protein sensor in pregnancy. Further studies in large clinical populations including fetal growth restriction are needed to discern whether FGF21 could be used as a marker for fetal nutrient insufficiency in the public health setting.
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Sutton, Elizabeth Frost, "Fibroblast Growth Factor 21 is a Novel Protein Sensor in Pregnancy" (2017). LSU Doctoral Dissertations. 4263.