Cold Induced Changes in White Adipose
Cold Induced Changes in White Adipose
An adaptation to a cold environment is a tendency to generate heat within our body. Some of
 this heat comes from our fat tissue. Although most fat tissue is "white fat", there are
 pockets deep within the body that are called "brown fat", which are specially adapted to
 burning fat and making heat. The investigator believes that our white fat, just underneath
 the surface of our skin, also has this property to burn fat and make heat, although not at
 the high level of brown fat. This study is to examine this fat-burning property of the white
 fat under the skin in response to seasons and to cold. Many such studies have been done in
 mice, but little has been done in humans.

 There are a number of factors, including age, weight, and medical history, that may make a
 person eligible or ineligible to participate in this study. Certain medications could make a
 person ineligible, but if these medications can be safely altered, the individual may become
 eligible.
Metabolic syndrome is a condition involving elevated levels of fat in the blood, a tendency
 towards diabetes, hypertension, and too much fat around the abdomen (an increased waistline).
 Individuals with metabolic syndrome often have impaired glucose tolerance, which is a
 condition where blood sugar is normal before a person eats, but is too high after drinking a
 sugary drink. This is due to an abnormality in the body's sensitivity to insulin (insulin
 resistance), which is due in part to an inability of muscle to take up glucose. People with
 metabolic syndrome have inflammation in their fat tissue and this inflammation in the fat
 tissue may impair the ability of the white fat to burn fat and continue to promote obesity.

 This study involves three arms. A propranolol with biopsy arm, a heavy water with biopsy arm,
 and a biopsy only arm. The goal is to understand the response of fat to cold, either acutely,
 or after repeated cold exposure, or in response to a change in seasons.

 Individuals (subjects) accepted into the study will report to the UK Center for Clinical and
 Translational Science (CCTS) research unit for baseline testing and repeated procedures.
 Participants will then be asked to have the same procedures done approximately 6 months
 later.

 Subjects enrolled into the study will need to come to the CCTS Unit for multiple visits. Most
 of these visits will be less than 1 hour, but 6 visits will involve procedures and will vary
 in time ranging from 4 hour to 6 hours. If a subject participates in all aspects of the study
 (fat biopsy from multiple depots, short term, long term, and seasons, then their total
 participation will be approximately 28 visits over 6-7 months. However, for most subjects,
 their participation will involve fewer visits, at the discretion of the principal
 investigator.

 The first visit will involve the consent process, followed by baseline fasting blood samples
 and the oral glucose tolerance test. If the subject passes these screening procedures, then
 subsequent visits will involve the fat biopsies, DEXA, and other visits described below.

 Fat biopsies (Visits 2, 14, 17 and 28). Regardless of the study arm assigned to all subjects
 will present to the CCTS fasting and a baseline fat biopsy will be performed on the thigh and
 lower abdomen. Abdominal and thigh subcutaneous adipose tissue will be removed by incision
 under local anesthesia. An ice pack will then be placed on the opposite thigh and lower
 abdomen for 30 min; 4 hr later, an adipose biopsy will be obtained from the iced area. The
 subject will then report to the CCTS daily for repeated 30 min ice pack procedures. However,
 at the discretion of the PI, participant may be able to perform the 30 min ice pack procedure
 at home. On day 7 and on day 14, subjects will report to the CCTS fasting and the above
 procedure will be repeated: an ice pack will be placed on the thigh and abdomen for 30 min,
 and fat biopsies will be taken from the iced area and from the non-iced area 4 hr later.

 Propranolol Arm: Subjects who qualify for this subgroup will be given propranolol 10 mg three
 times per day. If they tolerate the medication well with no side effects, after 5 days, they
 will then increase the dose to 20 mg three times per day. If they tolerate the 20 mg dose
 well with no side effects, after another 5 days (day 10), they will then increase the dose to
 40 mg three times per day and stay on this for the duration of the study.

 Heavy Water Arm: Subjects who qualify for this subgroup will be given heavy water (at visit
 2) every 3 hours for the next 12 hours while at the CCTS. They will then be sent home with
 doses of heavy water in sealed sterile vials, and will take one vial of heavy water twice per
 day for 5 weeks.

 The following test and procedures will be performed on subjects:

 Glucose tolerance test (Visits 1 and 15). This will be a standard oral glucose tolerance test
 using 75 g of glucose, with blood for glucose and insulin drawn at times 1, 30, 60, 90, and
 120 min.

 Resting metabolic rate. The investigator will measure resting metabolic rate (RMR). RMR is
 measured early in the morning, fasting, in a room on the CCTS.

 DEXA. Body composition will be measured with DEXA.

 12-Lead ECG: To examine heart rhythm and heart rate and any evidence of previous heart
 disease.

 Urine Collection: Females who are capable of becoming pregnant will also be given a urine
 pregnancy test. If the test results show that they are pregnant they will not be able to
 participate in the study.

 Unscheduled Visits: During the study if either the subject or the PI feel that that the
 subject should be seen for an additional visit due to an adverse event, the study staff will
 arrange for this visit. This visit should take no more than 30 minutes. During this visit the
 investigator will:

 -  Review subject's current medication use, including over the counter medications and
 herbals.

 -  Ask the subject questions about their health or any problems they may have had since
 their last visit.

 -  If necessary, take a blood sample (about 1 tablespoon) and urine sample (about 6
 teaspoons) to monitor the subject's general health.

 -  If necessary, perform a ECG and measure blood pressure and pulse.

 -  If necessary, ask questions about how study drug dosing at home.

 After completing the above procedure, the subject will be asked to come back for the same set
 of procedures the following season (i.e. winter, if original procedure was summer, or vice
 versa).

 Therefore, if the subject completes all the procedures in both seasons, a total of 16
 biopsies will be performed. Following initial studies, the investigator may refine the
 protocol and take fewer biopsies. For example, if early experiments determine that abdominal
 fat is not responsive to seasons, the investigator may discontinue this procedure. The
 investigator may determine that the baseline fat biopsy (prior to icing) is unnecessary.
Inclusion Criteria:

 -  the lean subjects body mass index (BMI) < 27

 -  subjects with obesity/MetS (BMI 27-45 with IGT, IFG, or 3 features of MetS)

 -  Insulin resistance Fasting blood sugar >126, or 2 hr glu >200, but with A1C<7.5 (i.e.
 we will include subjects with T2DM on no meds and with good glycemic control)

 -  adequate platelet count (>100,000)

 -  hematocrit of >32

 -  stable weight

 Exclusion Criteria:

 -  obese subjects (BMI > 45)

 -  anti-inflammatory drugs, β-blockers, any diabetes drugs or drugs known to affect
 adipose tissue

 -  an unstable medical condition

 -  coronary artery disease

 -  congestive heart failure

 -  heart block or a history of or any contraindication to a β-blocker.

 -  asthma

 -  previous stroke

 -  use of anticoagulants or aspirin

 -  pregnant or breastfeeding

 -  lifestyles involving absent or extreme temperature exposure (eg. homebound or
 institutionalized subjects, outdoor workers).