ACCESSION NO: 0436300  SUBFILE: CRIS 

PROJ NO: 3092-51000-065-01S AGENCY: ARS 3092 

PROJ TYPE: USDA COOPERATIVE AGREEMENT PROJ STATUS: NEW 
CONTRACT/GRANT/AGREEMENT NO: NOT APPLICABLE 
START: 01 APR 2019 TERM: 30 SEP 2020

INVESTIGATOR: CHANDLER L D; MARINI J; FIOROTTO M; BURRIN D G; DAVIS T A

PERFORMING INSTITUTION: 
BAYLOR COLLEGE OF MEDICINE 
HOUSTON, TEXAS 77030

IMPACT OF PERINATAL NUTRITION ON METABOLIC HEALTH AND DISEASE PREVENTION

CLASSIFICATION
KA Subject Science Pct
702 6010 1010 100

CLASSIFICATION HEADINGS:  R702 . Requirements and Function of Nutrients and Other Food
Components; S6010 . Individuals; F1010 . Nutrition and metabolism

BASIC 100%    APPLIED 0%    DEVELOPMENTAL 0%

OBJECTIVES: Objective 1: Determine the effect of enteral nutrition on FGF19 secretion and the
activation of FGF19 receptors and downstream signaling pathways and metabolism in various tissues in
neonatal pigs. Objective 2: Determine whether increased FGF19 availability using parenteral
administration of porcine FGF19 and oral FXR agonist treatment controls the rate of growth, tissue protein
synthesis and intestinal development in neonatal pigs. Objective 3: Determine whether being born
prematurely blunts the protein and glucose metabolic responses to the feeding-induced rise in amino
acids and insulin and identify the mechanisms involved. Objective 4: Identify the mechanisms by which
amino acids, particularly leucine and its metabolites, regulate protein synthesis, degradation, and
accretion and how these responses change with development. Objective 5: Identify the mechanisms
(molecular and metabolic) that limit citrulline production in premature, neonatal, and young pigs of both
sexes; determine the basis for the greater citrulline production observed in females and determine the
utilization of citrulline for endogenous arginine synthesis in vivo at different developmental stages.
SubObjective 5A: Identify the molecular and metabolic mechanisms that limit citrulline production in
premature, neonatal, and young pigs of both sexes; and to determine the basis for the greater citrulline
production observed in females. SubObjective 5B: To determine the utilization of citrulline for endogenous
arginine synthesis in vivo at different developmental stages. Objective 6: Establish the molecular
mechanisms and functional significance of differences in gene expression identified in satellite cell-
derived myoblasts isolated from the offspring of dams fed a low-protein versus an adequate protein diet
over critical windows of postnatal development. Objective 7: Determine the impact of maternal dietary
protein level during lactation on biomarkers of one-carbon metabolism in their offspring and establish if
the observed effects translate into differences for DNA methylation and/or histone post-translational
modifications in satellite cell-derived myoblasts isolated from the skeletal muscles of these offspring.

APPROACH: Despite improvements in their nutritional management, most premature and low birth
weight infants have experienced growth faltering by discharge. Many remain small to adulthood and are
at an increased risk for developing metabolic diseases such as obesity and type 2 diabetes. The goal of
this project is to identify the mechanisms that regulate the diminished growth and altered metabolic
responses to nutrition in premature and low birth weight infants and to develop new nutritional strategies
to optimize their growth and development. Our approach will be to use neonatal piglet and rodent models
to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic
response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean
growth. We will determine the role of the enterokine, FGF19, in the anabolic response to enteral feeding
in the preterm and whether augmentation of its secretion will enhance growth and metabolic function. We
will identify mechanisms that limit citrulline production and the impact of gender and age. We will establish
the mechanisms by which undernutrition during critical windows of postnatal development impacts
proliferation of skeletal muscle stem cells and the mature muscle nuclear number. Further we will test
whether methyl group deficiency induced by inadequate amino acid supply results in permanent
epigenetic modifications that impact muscle growth. This project is expected to have a positive impact by
providing novel information that will be directly useful in optimizing the nutritional management of
premature and low birth weight infants and improving their long-term metabolic health and growth.

KEYWORDS: ENTERAL NUTRITION FGF19 NEONATAL PARENTERAL PORCINE PREMATURE

INFANTS AMINO ACID LEUCINE PROTEIN SYNTHESIS CITRULLINE ARGININE IN VIVO ARGININE
MYOBLASTS DNA METHYLATION HISTONE SKELETAL MUSCLE TYPE 2 DIABETES LOW BIRTH
WEIGHT GROWTH ANABOLIC LEUCINE LEAN ENTEROKINE STEM CELLS METHYL

PROGRESS: 2018/10 TO 2019/09
Progress Report Objectives (from AD-416): Objective 1: Determine the effect of enteral nutrition on
FGF19 secretion and the activation of FGF19 receptors and downstream signaling pathways and
metabolism in various tissues in neonatal pigs. Objective 2: Determine whether increased FGF19
availability using parenteral administration of porcine FGF19 and oral FXR agonist treatment controls the
rate of growth, tissue protein synthesis and intestinal development in neonatal pigs. Objective 3:
Determine whether being born prematurely blunts the protein and glucose metabolic responses to the
feeding-induced rise in amino acids and insulin and identify the mechanisms involved. Objective 4:
Identify the mechanisms by which amino acids, particularly leucine and its metabolites, regulate protein
synthesis, degradation, and accretion and how these responses change with development. Objective 5:
Identify the mechanisms (molecular and metabolic) that limit citrulline production in premature, neonatal,
and young pigs of both sexes; determine the basis for the greater citrulline production observed in
females and determine the utilization of citrulline for endogenous arginine synthesis in vivo at different
developmental stages. SubObjective 5A: Identify the molecular and metabolic mechanisms that limit
citrulline production in premature, neonatal, and young pigs of both sexes; and to determine the basis for
the greater citrulline production observed in females. SubObjective 5B: To determine the utilization of
citrulline for endogenous arginine synthesis in vivo at different developmental stages. Objective 6:
Establish the molecular mechanisms and functional significance of differences in gene expression
identified in satellite cell-derived myoblasts isolated from the offspring of dams fed a low- protein versus
an adequate protein diet over critical windows of postnatal development. Objective 7: Determine the
impact of maternal dietary protein level during lactation on biomarkers of one-carbon metabolism in their
offspring and establish if the observed effects translate into differences for DNA methylation and/or
histone post-translational modifications in satellite cell-derived myoblasts isolated from the skeletal
muscles of these offspring. Approach (from AD-416): Despite improvements in their nutritional
management, most premature and low birth weight infants have experienced growth faltering by
discharge. Many remain small to adulthood and are at an increased risk for developing metabolic
diseases such as obesity and type 2 diabetes. The goal of this project is to identify the mechanisms that
regulate the diminished growth and altered metabolic responses to nutrition in premature and low birth
weight infants and to develop new nutritional strategies to optimize their growth and development. Our
approach will be to use neonatal piglet and rodent models to fill these knowledge gaps. We will determine
whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by
which amino acids, particularly leucine, regulate lean growth. We will determine the role of the enterokine,
FGF19, in the anabolic response to enteral feeding in the preterm and whether augmentation of its
secretion will enhance growth and metabolic function. We will identify mechanisms that limit citrulline
production and the impact of gender and age. We will establish the mechanisms by which undernutrition
during critical windows of postnatal development impacts proliferation of skeletal muscle stem cells and
the mature muscle nuclear number. Further we will test whether methyl group deficiency induced by
inadequate amino acid supply results in permanent epigenetic modifications that impact muscle growth.
This project is expected to have a positive impact by providing novel information that will be directly useful
in optimizing the nutritional management of premature and low birth weight infants and improving their
long-term metabolic health and growth. This project was only recently certified by OSQR thus no progress
has been made at this time.

PUBLICATIONS (not previously reported): 2018/10 TO 2019/09

No publications reported this period.

SUPPLEMENTARY DATA:  Institution Type: USDA  Region: 2  Process Date: 2019/08/15  Progress

Update: 2020/03/19  Program Code: NOT APPLICAB