Altered lipid partitioning in youth: Examining the dietary determinants and cardiometabolic consequences Restricted; Files Only

Cioffi, Catherine (Spring 2020)

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The high prevalence of obesity and related cardiometabolic disease (CMD) risk factors in children is an alarming public health issue world-wide. However, evidence suggests that it is not obesity itself that drives CMD, but instead the distribution of fat throughout the body. Greater upper-body fat, especially as abdominal visceral and hepatic fat, is strongly associated with CMD risk, but the etiology of body fat distribution, and the mechanisms that contribute to future disease risk are poorly understood.

Therefore, the purpose of this dissertation was to clarify the complex inter-connections between diet quality, body fat distribution, and cardiometabolic dysfunction in youth. First, we examined associations of added sugar intake with upper-body fat partitioning, measured as a trunk-to-leg fat ratio (TLR), in a nationally-representative sample of adolescents. This analysis showed that added sugar from sugar-sweetened beverages (SSBs), but not all sources, was associated with higher TLR, even when adjusting for total calories, suggesting an energy balance-independent link between SSBs and body fat distribution 

Second, in order to elucidate the mechanisms linking central fat to CMD risk, we assessed the differential clinical and molecular networks associated with individual upper-body fats (including abdominal visceral and subcutaneous fat and hepatic fat) in youth. This showed that hepatic fat was a stronger correlate of key CMD risk factors, including insulin resistance (IR) and dyslipidemia, compared to abdominal fats. On the molecular level, hepatic fat also correlated with systemic disturbances in the plasma metabolome, especially related to amino acid and lipid pathways, which may provide insight into biological processes underlying hepatic fat-induced metabolic dysregulation.

Lastly, using data from an 8-week, randomized controlled trial in boys, we examined whether these disturbances in the plasma metabolome were responsive to a therapeutic hepatic fat reduction induced by a low-free sugar diet (<3% of total energy intake). In this study, the diet treatment was associated with changes in several metabolic pathways, including key amino acid pathways (e.g. serine and tryptophan metabolism), and lipid pathways (e.g. fatty acyl, ketone, and glycerophospholipid metabolism). However, there were no changes in other hypothesized pathways, such as the branched chain amino acids and related metabolites, which may relate to the finding that IR was only slightly improved in the diet treatment group, and suggests that a longer study duration and/or larger hepatic fat reduction may be needed to observe a normalization in these biological processes.

The work in this dissertation makes an important contribution to the growing body of research on altered fat partitioning in youth, the potential dietary determinants, and the cardiometabolic consequences. The main findings support that SSB intake correlates with greater upper-body fat deposition; in turn, upper-body fat spillover as hepatic fat is more strongly associated with cardiometabolic dysfunction than abdominal fats. Finally, several of these abnormalities may be normalized by a diet-induced reduction in hepatic fat. Thus, hepatic fat warrants further attention as a mediating factor in diet-CMD associations and may be an effective therapeutic target for disease prevention and treatment interventions.

Table of Contents

Table of Contents

Chapter 1: Introduction

Chapter 2: Background

2.1 . Significance of the problem:

2.2 . Body fat distribution in childhood metabolic dysfunction:

2.3 . Determinants of body fat distribution:

2.4 . High-Resolution Metabolomics: Opportunities and Applications

2.5 . Summary, specific aims, and hypotheses:

Chapter 3: Methods

3.1 . Introduction:

3.2 . Overview of Parent Studies:

3.3 . Dietary Assessment Methods:

3.4 . Body Composition Assessment Methods:

3.5 . High-Resolution Metabolomics Methods:

3.6 . Statistical and Bioinformatics Analyses:

Chapter 4: Associations of added sugar from all sources and sugar-sweetened beverages with regional body fat deposition in U.S. adolescents: NHANES 1999–2006

4.1 . Abstract:

4.2 . Introduction:

4.3 . Methods:

4.4 . Results:

4.5 . Discussion:

Chapter 5: Hepatic fat is a stronger correlate of key clinical and molecular abnormalities than abdominal visceral and subcutaneous fat in youth

5.1 . Abstract:

5.2 . Introduction:

5.3 . Methods:

5.4 . Results:

5.5 . Discussion:

Chapter 6: Plasma metabolomic patterns associated with a diet-induced reduction in hepatic fat among adolescent boys

6.1 . Abstract:

6.2 . Introduction:

6.3 . Materials And Methods:

6.4 . Results:

6.5 . Discussion:

Chapter 7: Conclusions

7.1 . Key conclusions:

7.2 . Public health implications:

7.3 . Future directions for research:

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