Maternal and Dietary Influences on Offspring Growth and Body Composition among Female Rhesus Macaques (Macaca mulatta) Open Access

Mummert Anixter, Amanda Lee (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/ns064664j?locale=en
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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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