## Protocol Section
### Identification Module
**NCT ID:** NCT06424132

**Brief Title:** Thermogenic Silencer Regulatory Factors in Humans

**Official Title:** Identification of Thermogenic Silencing Regulatory Factors as Biomarkers of Metabolic Health in Humans

#### Organization Study ID Info
**ID:** PCO1051
#### Organization
**Class:** OTHER
**Full Name:** Rockefeller University
### Status Module
#### Completion Date
**Date:** 2027-05

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-21

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-15

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-05

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-05

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-21
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-10
**Study First Submit QC Date:** 2024-05-15
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** Cornell University

#### Lead Sponsor

**Class:** OTHER

**Name:** Rockefeller University

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**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 Module

**Conditions:**

- Obesity

- Metabolic Disease

- Cold Exposure

### Design Module

#### Design Info

**Allocation:** NON_RANDOMIZED

**Intervention Model:** CROSSOVER

**Intervention Model Description:** Participants in from the three different study groups (lean, obese, and obese with type 2 diabetes) will receive the same intervention: cold environmental exposure followed by a rewarming period

##### Masking Info

**Masking:** NONE

**Primary Purpose:** PREVENTION

#### Enrollment Info

**Count:** 120

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

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

**Intervention Names:**

- Other: Cold Vest Exposure Period

- Other: Rewarming Exposure Period

- Other: Fasting

**Label:** Obese group

**Type:** EXPERIMENTAL

#### Arm Group 2

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

**Intervention Names:**

- Other: Cold Vest Exposure Period

- Other: Rewarming Exposure Period

- Other: Fasting

**Label:** Obese group with Type II diabetes

**Type:** EXPERIMENTAL

#### Arm Group 3

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

**Intervention Names:**

- Other: Cold Vest Exposure Period

- Other: Rewarming Exposure Period

- Other: Fasting

**Label:** Lean group

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Lean group

- Obese group

- Obese group with Type II diabetes

**Description:** 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.

**Name:** Cold Vest Exposure Period

**Type:** OTHER

#### Intervention 2

**Arm Group Labels:**

- Lean group

- Obese group

- Obese group with Type II diabetes

**Description:** 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.

**Name:** Rewarming Exposure Period

**Type:** OTHER

#### Intervention 3

**Arm Group Labels:**

- Lean group

- Obese group

- Obese group with Type II diabetes

**Description:** 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.

**Name:** Fasting

**Type:** OTHER

### Outcomes Module

#### Primary Outcomes

**Description:** RNA sequencing to measure and identify a list of gene transcripts that are differentially expressed before and after re-warming. A true change is defined as 1.5 fold increase or decrease in gene expression.

**Measure:** Identification of adipose tissue transcriptome

**Time Frame:** Before and after 3-hour rewarming period.

**Description:** Proteins will be captured from blood and analyzed via mass spectrometry which generates a list of proteins for each sample. The investigators will compare the mean fold change (true change is greater than 1.5 fold) in protein abundance at the specified study time points.

**Measure:** Identification of cold and warm-regulated proteome.

**Time Frame:** Before and after 3 hour cold exposure period and before and after 3 hour rewarming period.

**Description:** Metabolites will be captured from blood and analyzed via mass spectrometry which generates a list of metabolites for each sample. The investigators will compare the mean fold change (true change is greater than 1.5 fold) in metabolite abundance at the specified study time points.

**Measure:** Identification of cold and warm-regulated metabolome.

**Time Frame:** Time frame will be before and after 3 hour cold exposure period as well as before and after 3 hour rewarming period.

#### Secondary Outcomes

**Description:** Diet History Questionnaire III (DHQ III) calculates Healthy Eating Index (HEI- integer with no units).

**Measure:** Nutritional assessments of individuals correlated to expression patterns of human silencer regulatory factors.

**Time Frame:** Baseline

**Description:** BMI is calculated by weight and height measured by anthropometric assessments, using the formula weight in kilograms divided by height in meters squared (kilograms/meter\^2).

**Measure:** Body Mass Index (BMI) correlated to expression patterns of human silencer regulatory factors.

**Time Frame:** Baseline

**Description:** Bod Pod uses Air Displacement Plethysmography (ADP) to determine body composition, the ratio of fat mass to lean mass. The investigators will measure fat mass composition in units of percentage (%).

**Measure:** Fat mass body composition (%) measured by Bod Pod correlated to expression patterns of human silencer regulatory factors.

**Time Frame:** Baseline

**Description:** Bod Pod uses Air Displacement Plethysmography (ADP) to determine body composition, the ratio of fat mass to lean mass. The investigators will measure lean mass composition in units of percentage (%).

**Measure:** Lean Mass body composition (%) measured by Bod Pod correlated to expression patterns of human silencer regulatory factors.

**Time Frame:** Baseline

### Eligibility Module

**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

**Healthy Volunteers:** True

**Maximum Age:** 35 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** jb2254@cornell.edu

**Name:** Joeva Barrow, Ph.D., R.D.

**Phone:** 607-255-9429

**Role:** CONTACT

**Contact 2:**

**Email:** pcohen@rockefeller.edu

**Name:** Paul Cohen, Ph.D., M.D.

**Phone:** 212-327-7918

**Role:** CONTACT

#### Overall Officials

**Official 1:**

**Affiliation:** The Rockefeller University and Cornell University

**Name:** Joeva Barrow, Ph.D., R.D.

**Role:** PRINCIPAL_INVESTIGATOR

**Official 2:**

**Affiliation:** The Rockefeller University

**Name:** Paul Cohen, Ph.D., M.D.

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Document Section

### Large Document Module

#### Large Docs

- Date: 2024-04-15

- Filename: Prot_SAP_000.pdf

- Has ICF: False

- Has Protocol: True

- Has SAP: True

- Label: Study Protocol and Statistical Analysis Plan

- Size: 2110725

- Type Abbrev: Prot_SAP

- Upload Date: 2024-04-26T13:28

- Date: 2024-04-15

- Filename: ICF_001.pdf

- Has ICF: True

- Has Protocol: False

- Has SAP: False

- Label: Informed Consent Form

- Size: 913958

- Type Abbrev: ICF

- Upload Date: 2024-04-26T13:23

## Derived Section

### Condition Browse Module - Browse Branches

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC01

- Name: Infections

- Abbrev: BC08

- Name: Respiratory Tract (Lung and Bronchial) Diseases

### Condition Browse Module - Browse Leaves

- ID: M12701

- Name: Obesity

- Relevance: LOW

- As Found: Unknown

- ID: M11639

- Name: Metabolic Diseases

- Relevance: HIGH

- As Found: Metabolic Diseases

- ID: M14978

- Name: Respiratory Tract Infections

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000008659

- Term: Metabolic Diseases

### Intervention Browse Module - Browse Branches

- Abbrev: Infl

- Name: Anti-Inflammatory Agents

- Abbrev: ARhu

- Name: Antirheumatic Agents

- Abbrev: Analg

- Name: Analgesics

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M207501

- Name: Chrysarobin

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
