There is increasing evidence that propensity for weight gain, adiposity and metabolic comorbidities can begin in the womb. Maternal nutrition, in particular adequate protein intake, is critical for normal fetal development and it is well established that malnutrition in utero leads to impaired fetal growth, low or high birth weight and with either phenotype, increased risk for obesity, diabetes and cardiovascular disease later in life. The protein leverage hypothesis describes a link between protein and energy intake and specifically demonstrates that protein intake is prioritized over other macronutrients. Protein deficiency therefore promotes counter regulatory mechanisms leading to adaptive increases in total energy intake until protein balance is restored. During gestation, protein demand is increase due to increases in total body protein turnover and protein deposition to the growing fetus and maternal tissues. With the increased protein demanded by gestation and without intentional dietary alteration, pregnant women may be exposing their fetus to unintentional protein restriction during gestation and this protein reduction may leverage an increase in energy intake and create an altered intrauterine environment for the fetus. While the specific mechanistic link(s) between protein sensing and energy intake have not been described, fibroblast growth factor 21 (FGF21) has been recently discovered to act as a novel endocrine signal in protein restriction with a robust increase in FGF21 and energy intake during protein dilution dietary studies. Thus the key objective of our proposal is to study the role of FGF21 as a mediator for the protein leverage hypothesis in utero.
Specific Aim 1 will test the hypothesis that FGF21 will be increased in pregnant women consuming reduced protein diets during gestation. Compellingly, fibroblast growth factor receptors (FGFRs) and ?-Klotho (cofactor to FGFR which enables FGF21 activity) have been identified in human placenta. Therefore, our second objective is to study whether the metabolic effects from FGF21 (i.e. alterations in nutrient transport) on tissues expressing ?-Klotho are present in the placenta. Accordingly, our Specific Aim 2 will test the hypothesis that FGF21 will modulate nutrient transport into the placenta. The results of the proposed studies will provide important new insight into the role of FGF21 in the protein leverage hypothesis during pregnancy and the metabolic plasticity of the placenta in response to variation in maternal protein intake. Equally important, completion of the outlined training plan by the applicant will supply the field with a well-trained, translational placental researcher who can apply the skills learned through this fellowship to advance the field of future placenta and developmental programming research.

Public Health Relevance

The proposed studies and predoctoral training plan will provide insight into the role of the placenta in nutritional programming. In particular, we will study fibroblast growth factor 21 (FGF21) as a potential signal in the protein leverage hypothesis in pregnancy. Successful completion of the outlined training plan by the applicant will supply the field with a well-trained, translational placental researcher who can apply the skills learned through this fellowship to an independent career within the fields of placental research, developmental programming, and reproductive science.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F06-S (20)L)
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Raiten, Daniel J
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Lsu Pennington Biomedical Research Center
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Baton Rouge
United States
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Sutton, Elizabeth F; Beyl, Robbie; Early, Kate S et al. (2018) Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell Metab 27:1212-1221.e3
Broskey, Nicholas T; Tam, Charmaine S; Sutton, Elizabeth F et al. (2018) Metabolic inflexibility in women with PCOS is similar to women with type 2 diabetes. Nutr Metab (Lond) 15:75
Sutton, Elizabeth F; Morrison, Christopher D; Stephens, Jacqueline M et al. (2018) Fibroblast growth factor 21, adiposity, and macronutrient balance in a healthy, pregnant population with overweight and obesity. Endocr Res 43:275-283
Sutton, Elizabeth F; Lob, Heinrich E; Song, Jiunn et al. (2017) Adverse metabolic phenotype of female offspring exposed to preeclampsia in utero: a characterization of the BPH/5 mouse in postnatal life. Am J Physiol Regul Integr Comp Physiol 312:R485-R491
Broskey, Nicholas T; Klempel, Monica C; Gilmore, L Anne et al. (2017) Assessing Energy Requirements in Women With Polycystic Ovary Syndrome: A Comparison Against Doubly Labeled Water. J Clin Endocrinol Metab 102:1951-1959
Sutton, Elizabeth F; Cain, Loren E; Vallo, Porsha M et al. (2017) Strategies for Successful Recruitment of Pregnant Patients Into Clinical Trials. Obstet Gynecol 129:554-559
Redman, Leanne M; Gilmore, L Anne; Breaux, Jeffrey et al. (2017) Effectiveness of SmartMoms, a Novel eHealth Intervention for Management of Gestational Weight Gain: Randomized Controlled Pilot Trial. JMIR Mhealth Uhealth 5:e133