Body Composition and Very-Low-Density-Lipoprotein-Triglycerides (VLDL-TG) Kinetics

Study Overview
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Brief Summary
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Context: Upper body obese (UBO) subjects are more likely to develop cardiovascular disease (CVD) than lower body obese (LBO) or lean. This may in part be caused by greater hepatic secretion of very-low-density-lipoprotein-triglycerides (VLDL-TG). Objective: To assess the impact of body composition and insulin sensitivity on basal VLDL-TG turnover in women.

Detailed Description
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Body composition is an important predictor of obesity related life-style diseases. Thus, preferential accumulation of adipose tissue in the abdominal region has been demonstrated to be associated with greater risk of developing CVD and insulin resistance than accumulation in lower body depots. The reason for this is not yet fully understood, but there are indications that upper body fat depots contain larger and more lipolytically active adipocytes resulting in an excess hepatic delivery of FFAs in upper body obese individuals. As several lines of experimental evidence as well as cross-sectional studies have demonstrated, elevated levels of FFAs affect the cardiovascular system unfavourably and are most likely a major contributor to insulin resistance. A prominent feature of insulin resistance is hypertriglyceridemia, primarily caused by increased levels of very-low-density-lipoprotein (VLDL)-TG. Even though lipolysis in subcutaneous adipose tissue accounts for the majority ( 75 %) of FFAs delivered to the liver, it is conceivable that excess release from visceral adipocytes in UBO individuals impacts VLDL-TG secretion. The reason for this is two-sided: First, upon entry into the liver, FFAs are reesterified to form VLDL-TG which is subsequently secreted. Studies in cell lines as well as whole body investigations in humans have demonstrated, that perturbations of FFA levels may directly affect VLDL-TG output by the liver. Second, elevated levels of FFAs may induce hepatic insulin resistance resulting in increased VLDL-TG output due to a loss of the inhibitory effect of insulin on VLDL-TG secretion. In theory, this combination of excess substrate availability coupled with an unfavorable hormonal milieu (hepatic insulin resistance) could result in increased VLDL-TG production in UBO subjects. A recent study by Mittendorfer et. al. support this notion, since weight loss in UBO women resulted in decreased VLDL-TG production, presumably caused primarily by a decrease in the supply of visceral fatty acids. Although findings from previous studies have been contradictory as to whether body fat distribution directly affects VLDL-TG clearance, in vitro findings suggest regional differences in lipoprotein lipase (LPL) activity between UBO and LBO women, and VLDL-TG clearance could also be modulated by differences in VLDL associated fatty acid oxidation. To our knowledge, the latter point has not previously been addressed. The purpose of this study was therefore to investigate differences in VLDL-TG kinetics in women with different body composition phenotypes. Our preliminary hypothesis was that UBO women produce and secrete greater amounts of VLDL-TG than their lower body obese (LBO) or lean counterparts. We also hypothesized, that peripheral clearance would be similar in all groups. Lastly, we wanted to investigate whether the more benevolent lipid profile seen in lean women could in part be a result of a more efficient channeling of VLDL derived fatty acids towards oxidation.

Official Title
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Impact of Body Composition on Very-Low-Density-Lipoprotein-Triglycerides Kinetics

Conditions
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Obesity, Insulin Resistance

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Woman Premenopausal Healthy Not taking medication Exclusion Criteria: Diabetes

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| 1<br>Premenopausal Upper Body Obese (UBO) women with waist-hip ratio > 0.85 and BMI > 28 | |
| 2<br>Premenopausal Lower Body Obese (LBO) women with waist hip ratio < 0.8 and BMI > 28 | |
| 3<br>Premenopausal lean women with BMI < 25 | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VLDL-TG kinetics were assessed using a bolus injection of ex-vivo labeled [1-14C]VLDL-TG |  | Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| fractional VLDL-TG derived fatty acid oxidation was measured by 14CO2 trapping from expired air |  | Hours | 
| VLDL-TG fat deposition by adipose tissue biopsies |  | Hours | 
| Insulin sensitivity by the hyperinsulinemic-euglycemic clamp technique |  | 2 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VLDL-TG kinetics, Obesity, Body composition, Tracers, Tissue biopsies