Gene Expression and Inflammation in Overweight Subjects
Condition: Obesity; Inflammation; Nutrition Therapy
MeSH terms: Overweight; Inflammation
Study type: Observational

Summary: 
      This study will look at gene expression (whether particular sets of genes are activated
      ["turned on"] or deactivated ["turned off"]) in overweight people as compared to
      non-overweight individuals. It will also investigate the potential role of inflammatory and
      protective substances that are produced naturally by the body within fat tissue. Findings
      from the study may lead to the development of ways to predict who will respond best to diet
      therapy.

      Healthy individuals between 25 and 45 years of age may be eligible for this study. Overweight
      subjects must have a BMI of 25 to 40, and non-overweight control subjects a BMI of 19 to
      24.9. Candidates are screened with a medical history, physical examination, blood tests and
      electrocardiogram (EKG). They are instructed to record their dietary intake for a 3-day
      period and to collect their urine for a 24-hour interval.

      Participants have their food records reviewed a week after the screening visit. They are then
      scheduled for an overnight admission to the Clinical Center. Non-overweight subjects have one
      or two inpatient stays; overweight subjects have six inpatient stays plus frequent nutrition
      counseling sessions. During the 2-day hospital admissions, the following studies are
      performed:

        -  DEXA scan to determine the percentage of body fat tissue. The subject lies on a table
           for about 15 to 60 minutes while the body composition is measured with very low-dose
           x-rays.

        -  Single-slice CT scan to compare the amount of fat tissue under the skin with that in the
           abdomen. The subject lies on a table for about 5 to 10 minutes while the CT scanner
           measures body composition with very low-dose x-rays.

        -  Subcutaneous fat microdialysis to investigate how weight loss affects the activity of
           fat tissue. A small tube (catheter) is placed into the fat tissue under the skin of the
           abdomen after numbing the skin with a local anesthetic. Fluid samples are collected
           through the tube. The procedure lasts overnight. In five non-overweight controls, a
           small amount of a substance called leukotriene B4 is put into their fat tissue to help
           adjust the instruments used in the study.

        -  Air-displacement plethysmography to measure body composition. Subjects wear
           close-fitting clothing and enter a small capsule called a Bod-Pod. They breathe normally
           in the capsule while their body fat composition is studied.

        -  Blood tests. Blood samples are drawn to analyze thyroid hormones, lipids, glucose,
           electrolytes, clotting factors, kidney function, red cells and DNA.

        -  Euglycemic-hyperinsulinemic clamp to measure the effects of insulin in the body and to
           derive an index of insulin-sensitivity. Catheters are placed in a vein in an arm and in
           a vein in the hand on the other side of the body. Insulin and glucose are infused
           through the catheter in the arm, and blood samples are drawn from the catheter in the
           hand every 5 minutes to measure glucose levels. The test lasts about 2 hours.

        -  Subcutaneous fat biopsy to find out how weight loss affects fat tissue characteristics,
           gene regulation and the ability to store glucose. A small sample of fat tissue is
           obtained from the skin of the abdomen after numbing the area with an anesthetic.

        -  Nutrition counseling for overweight subjects. A nutritionist reviews the food record and
           designs a personalized diet for each participant.

        -  Weight loss intervention for overweight subjects. In addition to individual nutritional
           counseling, group sessions are provided every 2 weeks during the first 3 months of the
           study and then every month.
    

Detailed description: 
      Obesity is a global public health problem of epidemic proportions. It is the source of
      considerable morbidity and early mortality in the U.S. and is associated with increased risk
      of diabetes, hypertension, cardiovascular disease, and cancer.

      In recent years, new and evolving concepts have emerged regarding obesity as a chronic
      endocrine disorder of inflammation. Moreover, a growing body of evidence indicates that
      obesity alters the profile of a constellation of genes and that some changes in biomarkers of
      inflammation and gene expression can be reversed by weight loss.

      In this clinical protocol, we propose to test the idea that a particular set of genes is
      activated (or deactivated) in Overweight Subjects using standard microarray techniques on
      samples of subcutaneous adipose tissue derived from biopsies. In addition, we will study the
      local adipose tissue microenvironment by means of microdialysis. The role of a number of
      adipokines, inflammatory mediators/cytokines, and novel lipid products will be analyzed using
      sensitive Liquid Chromatography-Mass Spectrometry and ELISA methods.

      The study design incorporates two basic objectives:

        1. Comparison of Non-Overweight Controls vs. Overweight Subjects at Baseline and

        2. Correlation of changes in Overweight patients over time as they lose weight through a
           calorie-restricted diet.

      To these ends, 30 Non-Overweight Controls (BMI 19.0 24.9) and 80 Overweight Subjects (BMI
      25.0 45.0) will be enrolled. Baseline studies, to be obtained on all participants include:
      blood tests, anthropometric indices, body composition by air-displacement plethysmography,
      indirect calorimetry, intravenous glucose tolerance test as an index of insulin sensitivity,
      subcutaneous adipose tissue microdialysis, and subcutaneous adipose tissue biopsy. These
      procedures will require an overnight hospital admission to the Clinical Center. Overweight
      Subjects will then be prescribed a calorie-restricted diet and followed for one year. They
      will undergo repeat studies at regular, 3-month intervals to assess serial changes in the
      various parameters and to provide correlative data with the degree and rate of weight loss
      achieved.

      Taken together, these studies should shed light and provide fundamental insights into the
      nature of the altered gene expression and release of inflammatory cytokines and other
      mediators that characterize the overweight state and the dynamic series of events that take
      place when dietary intervention leads to weight loss. It is anticipated that a number of
      these changes will relate to macrophages and known inflammatory markers though doubtless
      there are other important leads yet to be discovered. Thus, our hope is that such studies
      will ultimately lead to the identification of novel genes that underlie the important
      metabolic derangements associated with obesity and their response to different treatment
      modalities.
    

Observational model: Cohort
Time perspective: Prospective
Keywords: Obesity; Adipose Tissue; Microarrays; Cytokines; Eicosanoids; Gene Expression; Adipokines; Inflammation; Weight Loss; Lipid Products