Gene Expression and Inflammation in Overweight Subjects

Conditions:Obesity Weight Loss
Therapuetic Areas:Endocrinology
Age Range:25 - 45
Start Date:June 19, 2006
End Date:June 26, 2018

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Gene Expression and Release of Inflammatory Mediators in Overweight Subjects Before and After Weight Loss

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

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

- 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

- 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.

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

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


- Age 25-45 years, male or female

- BMI 25.0-45.0 kg/m(2) for Overweight Subjects and 19.0-24.9 kg/m(2) for Non-Overweight

- Healthy, as determined by medical history and laboratory tests

- Written informed consent


- BMI less than 19.0 or greater than 45.0 kg/m(2)

- History or symptoms compatible with cardiovascular disease, including arrhythmias and
syncopal episodes, or use of prescription medications for heart conditions, strokes,
or peripheral vascular disease

- Allergy to lidocaine

- Pregnancy or breastfeeding

- Menopause or peri-menopausal period (FSH greater than 15 mIU/ml)

- Use of hormonal contraceptives or estrogen replacement therapy

- Alcohol (more than 2 drinks per day or CAGE greater than 2 questions and/or
current/regular use of drugs such as amphetamines, cocaine, heroin, or marijuana

- Current use of tobacco products (smoking or chewing)

- History of Diabetes Mellitus, either type 1 or 2, or Fasting Glucose greater than 126

- Use of cholesterol- or lipid-lowering drugs, or fasting serum lipids in range
requiring medication per Adult Treatment Panel III recommendations of the National
Cholesterol Education Program

- Liver disease or ALT serum level greater than two-fold above the laboratory reference

- Renal insufficiency or estimated creatinine clearance less than or equal to 50 ml/min

- Current use of medications, dietary supplements (including fish oils), or alternative
therapies known to alter thyroid function with the exception of occasional use of
NSAIDs (3 tablets/week maximum) and Benzodiazepines; use of NSAIDs in the 10 days
preceding the hospital admissions

- Current history, symptoms, or behavior compatible with psychiatric disorders or
therapy with psychotropic medications that would be incompatible with safe and
successful participation in this study

- History of drug or alcohol abuse within the last 5 years; current use of drugs or

- Keloid formation (relative to subcutaneous adipose tissue biopsies)

- Hypo- or hyperthyroidism (TSH greater than or equal to 10; less than or equal to 0.1

- Blood pressure greater than 160/95 mm Hg or use of prescription medications for
treatment of hypertension

- Cushing Syndrome
We found this trial at
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, MD
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