Date

April 2009

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

The prevalence and severity of obesity is on the rise in adults and also devastatingly in children. Despite the similarities to adult obesity, a critical difference with childhood obesity is that the resulting metabolic disturbance may permanently disrupt normal development and increase susceptibility to these diseases independently of genetic factors and nutrition in adulthood. Critical periods exist in child development during which nutrition and health status may predispose the individual to body-weight regulation difficulties. Among these suggested periods is the in utero. Most of what we know about the development of metabolic systems and the impact of early maternal/nutritional manipulations has been obtained in rodent models which have a different ontogeny of these systems. The nonhuman primate, on the other hand, is an ideal model for such studies due to the remarkable similarities in development to the human. Specifically, we do not know the degree of impact of maternal consumption of high fat/calorie diets and maternal obesity on the development of fetal appetitive mechanisms in the brain. The goal of this dissertation was two-fold. First, I determined the normal ontogeny of the feeding-related neurocircuitry using a nonhuman primate model. Then, using a nonhuman primate model of diet-induced obesity, I determined the impact of maternal obesity on the fetal hypothalamic and midbrain neurocircuitry with a specific focus on body-weight regulation. Chapter 1 provides a review of the seminal literature that guided the direction of this work. The regulation of body-weight homeostasis is discussed with particular emphasis on hormonal and neuropeptide controls. The development of the pertinent homeostatic neurocircuitry is also reviewed in rodent models. Chapter 2 establishes the normal ontogeny of the important neuropeptides that regulate body-weight homeostasis. Since many of these hypothalamic neurons develop and begin to establish projections to other nuclei during the later trimesters (2nd and 3rd). Chapter 3 introduces the model of maternal diet-induced obesity. Nonhuman primates consumed either a normal fat diet (CTR) or a high fat/high calorie diet (HFD) for four years. In the fifth year, a subset of the HFD cohort was returned to CTR chow for a final pregnancy to determine the impact of “healthful eating” despite overt maternal obesity. Chapter 4 focuses on the influence of the maternal HFD on hypothalamic expression of feeding-related peptides and how the development of the projections is affected. Chapter 5 focuses on the midbrain contributions of forward projecting serotonin neurons. In these studies, pathways regulating serotonin metabolism are altered. Since serotonin neurons and the ensuing projections develop very early, serotonergic projections may be far more sensitive to the effects of diet manipulations than thought previously. Finally, Chapter 6 integrates the findings to one another and the relevance of these findings to human childhood obesity and modern clinical guidelines for pregnant women. In summary, these findings show that maternal high-fat diet consumption during pregnancy has ramifications on the in utero growth of the fetus. Even in the absence of gestational diabetes in these animals, maternal consumption of HFD may be more harmful than previously surmised.

Identifier

doi:10.6083/M4H41PDW

Division

Neuroscience Graduate Program

School

School of Medicine

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