Specific Aims
Neonatal programming influences the genetic regulation of a number of physiological systems from prenatal
life through adulthood, including behavior and metabolic responses to diet. Epidemiologic and genetic studies
suggest today’s obesigenic environment, defined by easy access to highly palatable, calorically dense foods
and sedentary recreation, either creates or unmasks maladaptive programming of growth that increases
susceptibility to obesity. Human studies have demonstrated: a) important contributions of fetal nutrition to birth
weight, b) a “U-shaped” relationship between birth weight and fat mass later in life, and c) correlation of early
life serum leptin concentrations and body fat later in life. Whereas rodent studies have demonstrated important
effects of intrapartum maternal dietary fat and calorie intake on the growth of the offspring, controlled trials of
dietary manipulations throughout human pregnancy are difficult to design and conduct. A nonhuman primate
translational animal model would provide important insights into causal links between maternal nutrition and
infant growth and metabolic health. To this end, we have produced a cohort of 35 male and female rhesus
monkey infants whose mothers were fed either a standard low fat, high fiber diet (LCD) or a high fat, high
sugar diet (HCD) during pregnancy and lactation. Birth weights correlated most strongly with maternal lean
body mass and were unrelated to the fat/calorie content of the maternal diet. Among infants raised by mothers
on the LCD, postnatal growth rate in the first year of life was associated with peripartum maternal fat accretion
and even more closely with maternal serum leptin concentrations. Despite similar early growth, altered
metabolism was confirmed in offspring of mothers receiving a HCD. At 1 month of age, their infants had higher
circulating triglyceride and lower high density lipoprotein concentrations than those born to mothers fed a LCD.
In order to evaluate a model of diet-induced neonatal programming, we propose two specific aims:
Specific Aim 1: Determine whether maternal intake of a HCD during gestation and lactation predicts that
prepubertal, female offspring will consume more calories, increase physical activity, and maintain a similar
body fat mass as offspring exposed to a maternal LCD. Additional evaluations will determine whether
infants of HCD-fed mothers dedicate more energy than infants of LCD-fed mothers to non-adipogenic
processes, including accelerated linear growth (with high circulating IGF-1), skeletal maturation, and
pubertal development. Insulin sensitivity, serum leptin and adiponectin concentrations, and markers of
systemic inflammation will be evaluated as early indicators of the presence of metabolically dysfunctional
fat that may not be detected by DEXA scanning, but present at higher levels in HCD-exposed infants.
Specific Aim 2: Compare the offspring of mothers fed either a HCD or LCD during gestation and lactation
in a cross-over trial*** to determine if early exposure to the HCD increases caloric intake of 2-year old
female progeny during a 6 month reintroduction to the HCD. It is hypothesized that offspring from mothers
fed a HCD will consume more calories than those from mothers fed a LCD at baseline and that this relative
hyperphagia will be exacerbated when a HCD is available. To determine whether early life exposure to
HCD accentuates other changes of energy expenditure or promotes metabolic dysregulation, the measures
outlined in specific aim 1 will be performed during and after treatment with the experimental HCD diet.
Measurement of insulin resistance will be optimized during and after the trial by employing a
hyperinsulinemic, euglycemic clamp.
The developmental origin of adult disease is a new avenue of study that promises novel insights into methods
of assessing risk for and preventing chronic diseases. The development of a non-human primate model of
neonatal programming is therefore an important advance that has broad utility throughout genetic,
developmental, behavioral, and medical science.