Integrated Clinical and Metabolic Phenotyping of Adults with Hidden Adiposity Open Access

Bellissimo, Moriah P. (Spring 2020)

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Obesity is a common medical condition characterized by excess body fat that leads to metabolic diseases including cardiovascular disease, type 2 diabetes, and some cancers. In addition to increased total body fat, visceral adipose tissue (VAT), fat stored intra-abdominally, is an independent contributor to metabolic disease risk. Clinical evaluation for obesity often uses body mass index (BMI), a ratio of weight to height. However, evidence indicates that metabolic health is heterogeneous and individuals with the same BMI can have vastly different comorbidities. As a result, use of BMI alone may inaccurately assess metabolic health of individuals. The purpose of this dissertation was to utilize body composition and fat distribution analysis to provide greater insight into metabolic health and obesity pathophysiology.

This dissertation included three cross-sectional studies with the following aims 1) leverage a large cohort of working adults (n=693) to investigate differences in diet quality scores and physical fitness levels between adults categorized as lean, as having normal weight obesity (NWO), or as having overweight-obesity; 2) in a subset of the cohort (n=179), compare the plasma metabolome between the body composition groups using high-resolution metabolomics (HRM); and 3) examine diet quality and body fat distribution between adults with CF (n=24) and age-matched healthy controls (n=25) and determine if these factors are related to clinical assessments.

Adults with NWO had lower physical fitness levels than lean adults and included more females than males. Reported diet quality was similar between NWO and lean adults, but higher diet quality was associated with lower body fat and VAT in all participants. HRM analyses detected metabolic perturbations that were not recognized by classic clinical laboratories. Adults with NWO had metabolomic profiles similar to adults with overweight-obesity, including upregulated linoleic acid metabolism and altered amino acid metabolism. Finally, in the clinical cohort, participants with CF reported lower diet quality scores compared to controls. One-third of adults with CF had NWO and participants with CF had more VAT than age-matched controls, which was related to fasting glucose levels and added sugar intake. Larger studies in longitudinal cohorts are needed to evaluate these relationships and confirm findings. 

Table of Contents

CHAPTER 1: Introduction    1

Specific Aims and Hypotheses    2

Chapter 1 References    5

CHAPTER 2: Background    8

Obesity Pathophysiology    8

Visceral Adiposity    9

Principles of Nutrition Assessment Applied to Research in Adiposity    10

Lifestyle Determinants Influencing Adiposity    11

Anthropometric Measures of Adiposity    13

Dual-Energy X-Ray Absorptiometry Assessment of Body Composition    14

Novel Biochemical Markers Linked to Adiposity    16

     Aminothiol Redox    16

     High-Resolution Metabolomics    17

Normal Weight Obesity    19

Cystic Fibrosis    21

Overall Goal and Significance    23

Overview of Chapters    23

Chapter 2 References    25

CHAPTER 3: Extended Methods    42

Specific Aims and Hypotheses    42

Methods Specific to Chapters 4 and 5    43

Center for Health Discovery (CHD) Study Overview    43

CHD Cohort Study Inclusion and Exclusion Criteria    44

CHD Participant Recruitment    45

Assessments    46

Methods Specific to Chapter 6    56

Integration of Nutritional Metabolomics with Bioenergetics in Cystic Fibrosis Study (BEAM-CF) Overview    56

Participant Selection    57

Assessments    59

Chapter 3 References    65

CHAPTER 4: Physical fitness but not diet quality distinguishes lean and normal weight obese adults    68

Abstract    69

Introduction    72

Materials and Methods    73

Results    77

Discussion    81

Chapter 4 References    86

CHAPTER 5: Plasma high-resolution metabolomics differentiates adults with normal weight obesity from lean individuals    106

Abstract    109

Introduction    110

Methods    111

Results    116

Discussion    119

Chapter 5 References    125

CHAPTER 6: Visceral adipose tissue is associated with poor diet quality and higher fasting glucose in adults with cystic fibrosis    144

Introduction    148

Materials and Methods    149

Results    153

Discussion    155

Chapter 6 References    160

CHAPTER 7: Discussion    177

Key Findings    177

Role of Diet Quality and Physical Fitness on Body Composition    179

Role of Sex on Body Composition    181

Novel Metabolic Pathways Linked to Body Composition    182

Clinical Implications and Future Directions for NWO    183

Clinical Implications and Future Directions for Cystic Fibrosis and Other Catabolic Illnesses    187

Strengths and Limitations    189

Conclusions    190

Chapter 7 References    191

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