Thermogenic Silencer Regulatory Factors in Humans

NCT ID: NCT06424132

Last Updated: 2025-03-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-08-16
• Study Completion Date: 2027-05-31

Brief Summary

A promising approach to correct the metabolic dysfunction associated with obesity is to activate brown fat non-shivering thermogenesis (NST). A critical limitation with NST as a therapeutic option, however, is that this beneficial process is silenced under human physiological temperature conditions and the mechanisms of how this occurs is unknown. This study will be the first to identify human NST silencing factors that may be targeted for the treatment of obesity and metabolic disorders.

Detailed Description

Obesity and associated metabolic diseases such as type 2 diabetes continue to be one of the leading causes of death worldwide, demanding additional research into novel treatments beyond our current options. One promising experimental approach to overcome the metabolic dysfunctions associated with obesity, such as insulin resistance and glucose imbalance, is to activate brown fat non-shivering thermogenesis (NST). Activated human brown adipose tissue (BAT) increases energy expenditure at a molecular level and is associated with both improved insulin tolerance and glucose homeostasis. A critical limitation with human brown fat as a therapeutic option, however, is that its beneficial metabolic potential is restricted in a silenced state under physiological temperature conditions for most of human life. The regulatory factors that govern this silencing process are completely unknown. While many groups continue to seek novel mechanisms to activate brown fat, this study presents a unique approach, aiming to decipher the mechanisms that govern human brown fat silencing. The study hypothesizes that if the regulatory factors that silence brown fat NST can be defined, then these factors can be targeted for ablation to eliminate the "off switch", thereby keeping brown fat in a constitutively active state. Identification of human NST silencing factors will be critical to unlocking the metabolic benefits of human brown fat and would represent promising treatment opportunities for type 2 diabetes and other obesity-related disorders. Understanding these relationships will allow for precision treatment opportunities for type 2 diabetes in the future.

The overall goal of this study is to unlock the metabolic benefits of human brown fat by defining the regulatory mechanisms that keep BAT in a silenced state. The study will generate the first human secretome (list of secreted proteins in blood) and transcriptome (list of gene transcripts in adipose tissue) compendium from human plasma and subcutaneous adipose tissue respectively which will be composed of target proteins, metabolites, and genes that are differentially expressed in response to NST silencing conditions. Top candidates from the profiling will then be functionally validated in human adipocytes for their role in NST silencing. The study will be an important resource for the field and will identify novel candidates that may harbor regulatory potential to govern the NST silencing process in humans. These factors can then be targeted to promote the constitutive activation of NST in order to overcome the metabolic dysfunction associated with obesity and metabolic disease. Given the invasive nature of direct human brown fat sampling, the study will instead interrogate circulating factors in human plasma as a proxy for metabolic health. In addition, the study will also obtain subcutaneous adipose tissue for RNA profiling to identify genes that are upregulated under NST-silenced conditions compared to cold exposure.

Conditions

Obesity; Metabolic Disease; Cold Exposure

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Obese group

Body Mass Index (BMI) is \> 30, Hemoglobin A1c (HgA1c) \<5.7%

Group Type: EXPERIMENTAL

Cold Vest Exposure Period

Intervention Type: OTHER

A cold vest will be placed on the participant which consists of a water-perfused wearable vest, size S-M or M-L with adjustable straps attached to a small 'cooler' reservoir to circulate cold water between the vest and the cooler (Polar Products, Stow, OH- Product link: www.polarproducts.com/polarshop/pc/CoolOR-13-Quart-System-with-Arctic-Chiller-p24757.htm) This product is safe and recommended by experimental guidelines for human BAT studies. Participants will be cold exposed for a period of 3 hours resting in a reclined position engaged in reading and/or digital entertainment of their choice.

Rewarming Exposure Period

Intervention Type: OTHER

Following cold exposure, the cold vests will be removed, and participants will be offered a warm blanket to ease the transition from cold back to warm temperatures. Participants will then be moved to an adjacent warm room maintained at 30 degrees celsius and asked to return to the resting position of their choice. Participants will then engage in reading and/or digital entertainment for a 3-hour warm exposure period.

Fasting

Intervention Type: OTHER

Participants will be requested to refrain from food and caloric drinks for 12 hours (starting at 8pm) prior to the study visit. Blood will then be drawn the following morning (between 8 and 9am) 30mins later following a breakfast meal (9:30am- 10am). Participants will be housed in a room with ambient temperature at 25 degrees celsius between the two blood draws.

Obese group with Type II diabetes

Body Mass Index (BMI) is \> 30, Hemoglobin A1c (HgA1c) is \>6.5%

Group Type: EXPERIMENTAL

Cold Vest Exposure Period

Intervention Type: OTHER

A cold vest will be placed on the participant which consists of a water-perfused wearable vest, size S-M or M-L with adjustable straps attached to a small 'cooler' reservoir to circulate cold water between the vest and the cooler (Polar Products, Stow, OH- Product link: www.polarproducts.com/polarshop/pc/CoolOR-13-Quart-System-with-Arctic-Chiller-p24757.htm) This product is safe and recommended by experimental guidelines for human BAT studies. Participants will be cold exposed for a period of 3 hours resting in a reclined position engaged in reading and/or digital entertainment of their choice.

Rewarming Exposure Period

Intervention Type: OTHER

Following cold exposure, the cold vests will be removed, and participants will be offered a warm blanket to ease the transition from cold back to warm temperatures. Participants will then be moved to an adjacent warm room maintained at 30 degrees celsius and asked to return to the resting position of their choice. Participants will then engage in reading and/or digital entertainment for a 3-hour warm exposure period.

Fasting

Intervention Type: OTHER

Participants will be requested to refrain from food and caloric drinks for 12 hours (starting at 8pm) prior to the study visit. Blood will then be drawn the following morning (between 8 and 9am) 30mins later following a breakfast meal (9:30am- 10am). Participants will be housed in a room with ambient temperature at 25 degrees celsius between the two blood draws.

Lean group

Body Mass Index (BMI) is between 18.5 and 24.9. Hemoglobin A1c (HgA1c) \<5.7%

Group Type: EXPERIMENTAL

Cold Vest Exposure Period

Intervention Type: OTHER

A cold vest will be placed on the participant which consists of a water-perfused wearable vest, size S-M or M-L with adjustable straps attached to a small 'cooler' reservoir to circulate cold water between the vest and the cooler (Polar Products, Stow, OH- Product link: www.polarproducts.com/polarshop/pc/CoolOR-13-Quart-System-with-Arctic-Chiller-p24757.htm) This product is safe and recommended by experimental guidelines for human BAT studies. Participants will be cold exposed for a period of 3 hours resting in a reclined position engaged in reading and/or digital entertainment of their choice.

Rewarming Exposure Period

Intervention Type: OTHER

Following cold exposure, the cold vests will be removed, and participants will be offered a warm blanket to ease the transition from cold back to warm temperatures. Participants will then be moved to an adjacent warm room maintained at 30 degrees celsius and asked to return to the resting position of their choice. Participants will then engage in reading and/or digital entertainment for a 3-hour warm exposure period.

Fasting

Intervention Type: OTHER

Participants will be requested to refrain from food and caloric drinks for 12 hours (starting at 8pm) prior to the study visit. Blood will then be drawn the following morning (between 8 and 9am) 30mins later following a breakfast meal (9:30am- 10am). Participants will be housed in a room with ambient temperature at 25 degrees celsius between the two blood draws.

Interventions

Cold Vest Exposure Period

A cold vest will be placed on the participant which consists of a water-perfused wearable vest, size S-M or M-L with adjustable straps attached to a small 'cooler' reservoir to circulate cold water between the vest and the cooler (Polar Products, Stow, OH- Product link: www.polarproducts.com/polarshop/pc/CoolOR-13-Quart-System-with-Arctic-Chiller-p24757.htm) This product is safe and recommended by experimental guidelines for human BAT studies. Participants will be cold exposed for a period of 3 hours resting in a reclined position engaged in reading and/or digital entertainment of their choice.

Intervention Type: OTHER

Rewarming Exposure Period

Following cold exposure, the cold vests will be removed, and participants will be offered a warm blanket to ease the transition from cold back to warm temperatures. Participants will then be moved to an adjacent warm room maintained at 30 degrees celsius and asked to return to the resting position of their choice. Participants will then engage in reading and/or digital entertainment for a 3-hour warm exposure period.

Intervention Type: OTHER

Fasting

Participants will be requested to refrain from food and caloric drinks for 12 hours (starting at 8pm) prior to the study visit. Blood will then be drawn the following morning (between 8 and 9am) 30mins later following a breakfast meal (9:30am- 10am). Participants will be housed in a room with ambient temperature at 25 degrees celsius between the two blood draws.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. Age between 18 years old and 35

2. Lean group: BMI is between 18.5 and 24.9. HgA1c <5.7%

3. Obese group: BMI is >30, HgA1c <5.7%

4. Obese group with Type II diabetes: BMI is >30, HgA1c is >6.5% If on oral medication for diabetes management, HgA1c may be < 6.5% The following medications are also acceptable: statins, aspirin, angiotensin-converting enzyme inhibitors (ACEi), and angiotensin receptor blockers (ARB).

Exclusion Criteria

1. Diabetes type I (self-report)

2. Diagnosis of thyroid disease (including goiter, hyperthyroidism, hypothyroidism, thyroiditis)(self-report)

3. Diagnosis with cancer including skin cancer (self-report)

4. Diagnosis or evidence of Raynaud's Syndrome or systemic sclerosis (self-report)

5. A recent diagnosis of Coronavirus Disease 2019 (COVID-19) (last 2 weeks) or hospitalized at the time of diagnosis with COVID-19

6. Any vaccine administration within two weeks preceding the study procedure

7. Currently pregnant

8. Currently taking any prescribed medication other than oral contraceptives. Treatments for weight loss or any other supplements that may alter weight or metabolism are not acceptable. Vitamins are acceptable.

9. Has consumed nicotine (smoking, inhaling, ingesting) within the last 6 months

10. Has used illicit drugs within the last 6 months (marijuana users are eligible unless consumed in the last 30 days).

11. Any medical, psychological, or social condition that, in opinion of principle investigators, would jeopardize the health or well-being of the participant during the study procedure or the integrity of the data

12. Diabetes Type II that is managed by insulin.

13. Steroid use in the last 30 days to the exclusions

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Cornell University

OTHER

Sponsor Role: collaborator

Rockefeller University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Joeva Barrow, Ph.D., R.D.

Role: PRINCIPAL_INVESTIGATOR

The Rockefeller University and Cornell University

Paul Cohen, Ph.D., M.D.

Role: PRINCIPAL_INVESTIGATOR

The Rockefeller University

Locations

Rockefeller University

New York, New York, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Joeva Barrow, Ph.D., R.D.

Role: CONTACT

jb2254@cornell.edu

607-255-9429

Paul Cohen, Ph.D., M.D.

Role: CONTACT

pcohen@rockefeller.edu

212-327-7918

Facility Contacts

Lucy Apicello

Role: primary

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

PCO1051

Identifier Type: -

Identifier Source: org_study_id