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Cold Induced Changes in White Adipose

Primary Purpose

Obese, Normal Body Weight, Prediabetes

Status
Completed
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Fat biopsy
Propranolol and fat biopsy
heavy water and fat biopsy
Sponsored by
Philip Kern
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Obese

Eligibility Criteria

35 Years - 60 Years (Adult)FemaleAccepts Healthy Volunteers

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).

Sites / Locations

  • University of Kentucky Medical Center Center for Clinical and Translational Science

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Active Comparator

Arm Label

Fat biopsy

Propranolol and Fat Biopsy

Heavy Water and Fat Biopsy

Arm Description

From each abdominal and thigh biopsy, between 0.5 - 3 g of tissue is obtained (often less from the thigh), which is used for immunohistochemistry and frozen for subsequent RNA or protein isolation.

From each abdominal and thigh biopsy, tissue will be examined for gene expression, with a focus on genes believed to be involved in adipose beiging (PGC1α, UCP1, TMEM26, IL4, Metrnl, CPA3, Siglec 8, tyrosine hydroxylase, others), and with immunohistochemistry, with a focus on beige adipocytes, macrophages, eosinophils and mast cells.

The investigator will measure in vivo adipose lipolysis and triglyceride (TG) turnover in response to cold to physiologically demonstrate the impact of cold exposure on tissue function. The subjects will then be given 50 mL sterile containers of 70% 2H2O and consume two 50 mL vials per day during the remainder of the 5-week labeling period. Plasma and urine will be collected weekly so that body 2H2O can be measured.

Outcomes

Primary Outcome Measures

WAT changes during repeated exposure to cold temperatures
Adipose biopsies will be performed
WAT changes following Propranolol dosing
Subjects will be prescribed propranolol and adipose biopsies will be obtained.
In vivo measurement of adipose lipolysis and triglyceride (TG) turnover
The heavy water will be given to and adipose biopsies will be obtained.

Secondary Outcome Measures

Full Information

First Posted
November 2, 2015
Last Updated
February 5, 2020
Sponsor
Philip Kern
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT02596776
Brief Title
Cold Induced Changes in White Adipose
Official Title
Cold Induced Changes in Human Subcutaneous White Adipose
Study Type
Interventional

2. Study Status

Record Verification Date
February 2020
Overall Recruitment Status
Completed
Study Start Date
March 2016 (undefined)
Primary Completion Date
August 20, 2018 (Actual)
Study Completion Date
August 20, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Philip Kern
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obese, Normal Body Weight, Prediabetes, Metabolic Syndrome

7. Study Design

Primary Purpose
Basic Science
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Fat biopsy
Arm Type
Active Comparator
Arm Description
From each abdominal and thigh biopsy, between 0.5 - 3 g of tissue is obtained (often less from the thigh), which is used for immunohistochemistry and frozen for subsequent RNA or protein isolation.
Arm Title
Propranolol and Fat Biopsy
Arm Type
Experimental
Arm Description
From each abdominal and thigh biopsy, tissue will be examined for gene expression, with a focus on genes believed to be involved in adipose beiging (PGC1α, UCP1, TMEM26, IL4, Metrnl, CPA3, Siglec 8, tyrosine hydroxylase, others), and with immunohistochemistry, with a focus on beige adipocytes, macrophages, eosinophils and mast cells.
Arm Title
Heavy Water and Fat Biopsy
Arm Type
Active Comparator
Arm Description
The investigator will measure in vivo adipose lipolysis and triglyceride (TG) turnover in response to cold to physiologically demonstrate the impact of cold exposure on tissue function. The subjects will then be given 50 mL sterile containers of 70% 2H2O and consume two 50 mL vials per day during the remainder of the 5-week labeling period. Plasma and urine will be collected weekly so that body 2H2O can be measured.
Intervention Type
Procedure
Intervention Name(s)
Fat biopsy
Intervention Description
up to 16 biopsy samples will be taken from each subject
Intervention Type
Drug
Intervention Name(s)
Propranolol and fat biopsy
Intervention Description
subset of subjects will receive propranolol and have fat biopsy performed
Intervention Type
Other
Intervention Name(s)
heavy water and fat biopsy
Intervention Description
subset of subjects will be given heavy water and have fat biopsy performed
Primary Outcome Measure Information:
Title
WAT changes during repeated exposure to cold temperatures
Description
Adipose biopsies will be performed
Time Frame
28 Weeks (Summer and Winter Seasons)
Title
WAT changes following Propranolol dosing
Description
Subjects will be prescribed propranolol and adipose biopsies will be obtained.
Time Frame
17 days in the summer season
Title
In vivo measurement of adipose lipolysis and triglyceride (TG) turnover
Description
The heavy water will be given to and adipose biopsies will be obtained.
Time Frame
5 weeks per season (summer and winter)

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Philip Kern, MD
Organizational Affiliation
University of Kentucky
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Kentucky Medical Center Center for Clinical and Translational Science
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
30089732
Citation
Finlin BS, Memetimin H, Confides AL, Kasza I, Zhu B, Vekaria HJ, Harfmann B, Jones KA, Johnson ZR, Westgate PM, Alexander CM, Sullivan PG, Dupont-Versteegden EE, Kern PA. Human adipose beiging in response to cold and mirabegron. JCI Insight. 2018 Aug 9;3(15):e121510. doi: 10.1172/jci.insight.121510. eCollection 2018 Aug 9.
Results Reference
result
PubMed Identifier
35894077
Citation
Thiagarajan D, Quadri N, Jawahar S, Zirpoli H, Del Pozo CH, Lopez-Diez R, Hasan SN, Yepuri G, Gugger PF, Finlin BS, Kern PA, Gabbay K, Schmidt AM, Ramasamy R. Aldose reductase promotes diet-induced obesity via induction of senescence in subcutaneous adipose tissue. Obesity (Silver Spring). 2022 Aug;30(8):1647-1658. doi: 10.1002/oby.23496.
Results Reference
derived

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Cold Induced Changes in White Adipose

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