Maternal and Dietary Influences on Offspring Growth and Body Composition among Female Rhesus Macaques (Macaca mulatta) Öffentlichkeit
Mummert Anixter, Amanda Lee (2016)
Abstract
Lifespan health potential originates in the first 1,000 days of human life. The developmental origins of health framework posits that alterations to physiology during this critical period have lasting effects on body form and function that in turn influence susceptibility to chronic disease across the life course. Incorporating evolutionary theory, this project investigated how intergenerational and environmental exposures during this critical period interact to influence fetal and infant growth trajectories as the mechanistic basis of the chronic disease. Previous research in humans suggest maternal morphology and psychosocial stress as exposures that interact with postnatal feeding strategies to influence growth. These factors are intertwined and reflective of larger societal circumstances in humans; translational animal models can reduce these subjectivities. Within this context, the present dissertation addresses how maternal body size and psychosocial stress, as naturally imposed through social subordination, are reflected in fetal and postnatal growth trajectories among female Rhesus macaques (Macaca mulatta), and whether subsequent morphology differs when challenged by a high calorie postnatal dietary intervention. The data used to address these aims came from a longitudinal sample of 35 female Rhesus macaque infants followed from mid gestation to six months of age, using anthropometry and dual energy X-ray absorptiometry (DXA) scanning to assess size and body composition. The results identified that intrauterine psychosocial stress exposure distinguishes offspring growth trajectories in the form of altered sensitivities to markers of maternal lifespan health (e.g., height, bone mineral content) and current energy balance (e.g., weight, BMI) that are not predicted by birth weight alone. In comparison to their peers, subordinate females challenged by a high calorie diet exhibit accelerated weight gain at the expense of skeletal integrity, setting the stage for susceptibility to overweight and compromised bone health. These data provide the first prospective longitudinal assessment of fetal and infant growth in Rhesus macaques, documenting an intergenerational pathway influencing the relative growth rates of alternate tissues with potential long-term effects on health. This suggests public health programs targeting girls and young women could have benefits that are measurable at generational timescales in the growth of their children.
Table of Contents
INTRODUCTION. 1
Overview of the Problem. 1
Shifting Health- and Diseasescapes and the Origins of Lifespan Health. 2
Leveraging Translational Animal Models. 5
Key Aims and Research Questions. 8
Dissertation Outline. 9
Introduction References. 10
Chapter 1 REVIEW OF THE LITERATURE. 20
Introduction. 20
Maternal Influences on Offspring Growth and Body Composition in Humans. 20
Maternal Body Size. 20
Maternal Psychosocial Stress. 23
Maternal Nutritional History and Infant Postnatal Feeding. 24
Translational Aspects of Nonhuman Primate Models for Understanding the Developmental Origins of Health. 25
Body Size and Obesity in Old World Primates. 27
Social Dominance Hierarchies as a Model of Chronic Psychosocial Stress. 30
˜Western Diets' and Controlled Dietary Interventions. 32
Review of Previous Work. 34
Maternal Morphology Effects on Offspring Size and Growth Trajectories. 34
Offspring Weight. 34
Offspring Crown-Rump Length and Body Composition. 36
Methodological Considerations Comparing Previous Work on Maternal Morphological Influences on Offspring Weight, Height, and Body Composition. 40
Maternal Social Rank Effects on Offspring Size and Growth Trajectories. 41
Offspring Weight. 42
Offspring Crown-Rump Length. 45
Offspring Body Composition. 46
Methodological Considerations Comparing Previous Work on Maternal Social Rank Influences on Offspring Weight, Height, and Body Composition. 50
‘Western' Dietary Intervention Effects on Offspring Size and Growth Trajectories. 54
Offspring Weight. 54
Offspring Crown-Rump Length and Crown-Heel Length. 56
Offspring Body Composition. 57
Summary and Discussion of Perinatal Dietary Influences on Offspring Morphology. 64
Conclusions and Future Directions. 65
Chapter 1 References. 70
Chapter 2 PRIMARY AIMS, HYPOTHESES, AND METHODS. 97
Primary Aims and Hypotheses. 97
Aim 1: To Identify Associations Between Maternal Rank, Maternal Body Composition, and Fetal Growth and Birth Weight Outcomes. 97
Aim 2: To Identify Associations Between Maternal Rank, Maternal Body Composition, Postnatal Diet, Birth Weight and Infant Growth Trajectories During The First 6 Postnatal Months. 97
Methods. 98
Study Design. 98
Study Subjects. 99
Study Procedures. 102
Phase 1. 102
Phase 2. 105
Statistical Procedures. 109
Funding. 111
Chapter 2 References. 112
Chapter 3 RESULTS. 115
Study Subjects. 115
Study Protocol. 116
Aim 1: To identify associations between maternal rank, maternal body composition, and fetal growth and birth weight outcomes. 116
Maternal Size and Body Composition During Pregnancy. 116
Maternal Rank Comparisons. 117
Fetal Size and Growth. 119
Neonatal Size and Maternal Effects. 121
Predictors of Crown-Heel Length at Birth. 125
Predictors of Weight/Crown-Heel Length at Birth. 127
Aim 2: To identify associations between maternal rank, maternal body composition, postnatal diet, birth weight and infant growth trajectories during the first 6 postnatal months. 129
Predictors of Postnatal Size and Growth Rates. 129
Chapter 3 References. 144
Chapter 4 DISCUSSION. 145
Summary of Findings. 145
Comparison of Results to Previous Studies in Old World Primates. 150
Social Rank. 151
Maternal Morphology. 151
High Calorie Diet. 153
Comparisons Across Studies. 153
Comparison of Results to Previous Studies in Humans. 156
Direct Correlations between Fetal and Infant Growth Rates. 157
Maternal Morphology, Fetal and Infant Size and Growth. 159
Maternal Psychosocial Stress, Fetal and Infant Size and Growth. 161
Comparisons Across Studies. 165
Proposed Mechanism: Social Subordination Induces Dysregulated Skeletal Metabolism In Utero with Consequences for Postnatal BMC Accrual and Weight Gain. 166
Skeletal Metabolism: Cross-Talk between Osteoblasts and Adipocytes. 168
Stem Cell Differentiation by PPARy: Balancing Osteoblast and Adipocyte Hormone Production. 168
Dysregulated MSC Differentiation: Implications for Metabolism. 169
Osteoblast Regulation of Bone Formation and Remodeling. 171
Osteocalcin: Synthesis and Bio-activation from Osteoblasts. 172
Osteocalcin: Functional Significance for Insulin Sensitivity in Rodents and Humans. 173
Chronic Glucocorticoid Exposure: Implications for Bone Mineralization and Skeletal Metabolism. 177
Regulation and Dysregulation of Glucocorticoid Production. 177
Critical Role of Glucocorticoids for Bone. 178
Glucocorticoid Excess Induces Frailty and Perturbed Metabolism. 179
Glucocorticoids in Normal Bone Formation and Growth. 180
Glucocorticoid Chronicity Impairs Normal Bone Formation and Growth. 181
Intrauterine Glucocorticoid Exposure: A Transgenerational Mechanism for Programming Skeletal Metabolism 182
Maternal-Fetal Regulation of Glucocorticoid Exposure.182
11ß-HSD2 Expression and Fetal Physiology. 184
Suppressed 11ß-HSD2 due to Chronic Social Subordination as a Mechanism for Health Risks. 185
Implications of a Glucocorticoid-based Pathway as a Mechanism for the Study Results and Other Observations among Nonhuman Primates. 187
Implications of a Glucocorticoid-based Pathway as a Mechanism for Observations among Human Infants. 189
Study Limitations. 190
Reflections on Primary Aims. 190
Aim 1: To identify associations between maternal rank, maternal body composition, and fetal growth and birth weight outcomes. 190
Aim 2: To identify associations between maternal rank, maternal body composition, postnatal diet, birth weight and infant growth trajectories during the first 6 postnatal months. 193
Reflections on Project Design. 193
Estimation of Gestational Age. 194
Model Assumptions. 194
Sample Size. 195
Timing of Maternal, Fetal, and Postnatal Anthropometry. 195
Specificity of Anthropometry, Study Team, and Researcher Participation. 196
Chapter 4 References. 198
Chapter 5 CONCLUSIONS. 228
Overview. 228
Theoretical Considerations and Implications. 228
Birth Weight is Not the Causal Mechanism. 230
Predictive Power of Fetal Anthropometry and Stabilizing Selection for Bone Form and Function. 231
Energy Sources for Bone Growth. 234
Translational Implications for Human Health. 236
Opportunities for Intervention. 237
Balancing Risks and Benefits: Failures When ˜Normal' Growth is Expected. 238
Chapter 5 References. 242
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