Neonatal programming of adult behavior and metabolism may be a mediator of the rising prevalence of obesity in the US. Programming is a developmental plasticity that uses exposures in early life to train complex biological processes towards optimal function in the anticipated future environment. Combined with modern lifestyles that have created a permissive "obesigenic" environment, maternal overnutrition during pregnancy and neonatal overfeeding are hypothesized to result in programming towards increased adiposity later in life and metabolic imbalances and inflammation that exacerbate obesity and its complications. Studies, mainly in rodents show that maternal ingestion of a high fat, high sugar, high calorie diet (HCD) during pregnancy and lactation programs behaviors and metabolism that promote obesity in the offspring. In rhesus monkeys, maternal body composition and gestational diet alter the growth and metabolism of the infants. To better study neonatal programming, a rhesus monkey model of obesity that allows measures of caloric intake while subjects live in their typical social housing, rather than in solitary cages has been developed. This proposal will study female rhesus monkeys born to mothers that were ad lib fed either a HCD or one that was low in fat and high in fiber (LCD) during pregnancy. We predict that throughout the study, infants exposed to a HCD during pregnancy and lactation will consume more food than those exposed to a LCD. Excess food consumption however may have a limited effect on the weight and body fat mass of young progeny, owing to compensatory increases in energy expenditure (physical activity, linear growth, or sexual maturation). Harmful accumulation of fat at visceral and ectopic sites is marked by insulin resistance and chronic inflammation that can become abnormal before body fat increases can be detected by DEXA scans. We will evaluate eating, physical activity, growth, maturation, insulin sensitivity, and inflammation in infants programmed by maternal HCD or LCD in fetal and early life and who were weaned to a LCD until age 20 months. We hypothesize that a HCD challenge at that point will augment changes programmed in the offspring by the maternal HCD and that prenatal HCD exposure will prolong the metabolic recovery after LCD is restored at 26 months. Outcomes to be measured include food intake (using a novel automated feeder), physical activity (accelerometry), growth (morphometric measurements and circulating IGF-1) and body composition (DEXA), skeletal (X-ray) and pubertal maturation (physical examination, serum progesterone), and measures of metabolically dysregulated adipose tissue, including insulin resistance (HOMA-IR, glucose clamp), circulating leptin and adiponectin, and markers of chronic inflammation (CRP, IL-6, TNF-?). A novel food dispenser will for the first time allow specific access for each subject to experimental diets and continuous monitoring of their ad lib caloric intake while they remain in their typical social housing. A nonhuman primate model of gestational overnutrition is a vital resource to explore the effects of weight on the health of mothers, children, and perhaps even subsequent generations.
The early life environment may affect an individual's predisposition to obesity and its complications much later in life. Proof of this hypothesis and therapeutic trials that exploit neonatal programming in humans require study designs that are challenging enough to mandate the proof of principle be first demonstrated in experimental animal models. Because most published research in this area is performed in rodents, its translation to humans is difficult. This proposal examines the effects of introducing a high fat, high sugar diet to pregnant and lactating rhesus monkeys on the growth and development of their prepubertal daughters.