## Protocol Section
### Identification Module
**NCT ID:** NCT06426082

**Acronym:** DEBATE

**Brief Title:** Deciphering a Novel and Unique Brown Adipose Tissue Depot in Women

**Official Title:** Deciphering the Molecular and Secretory Functions of a Novel and Unique Brown Adipose Tissue Depot in Women

#### Organization Study ID Info
**ID:** PID2022-141442OA-I00
#### Organization
**Class:** OTHER
**Full Name:** Universidad de Almeria
### Status Module
#### Completion Date
**Date:** 2026-08

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-23

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-20

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2025-08-31

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-11-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-23
**Type:** ACTUAL
**Study First Submit Date:** 2023-10-11
**Study First Submit QC Date:** 2024-05-20
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** Leiden University Medical Center

**Class:** OTHER

**Name:** ETH Zurich (Switzerland)

#### Lead Sponsor

**Class:** OTHER

**Name:** Universidad de Almeria

#### Responsible Party

**Investigator Affiliation:** Universidad de Almeria

**Investigator Full Name:** Borja Martínez Tellez

**Investigator Title:** Principal Investigator

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** Type of Study: Clinical Trial

Goal: The goal of this clinical trial is to investigate specific brown and beige fat cells in the dorsocervical area of young, lean adult women.

Participant Population/Health Conditions: The study will involve 40 young, lean adult women.

Main Questions: The main questions this study aims to answer are:

* Are there active brown or beige adipocytes in the subcutaneous fat of the dorsocervical area (i.e., iBAT)?
* What is the secretory function of these adipocytes?
* How do traditional interventions like cold exposure, as well as new approaches like Beta-2 agonist stimulation and exercise, affect the thermogenesis of these fat cells at the cellular and molecular levels?

Participants Will:

Be randomized into one of four groups: thermoneutral exposure, cold exposure, aerobic exercise, or Beta-2 agonist treatment.

Follow their assigned regimen for 4 weeks. Provide tissue samples from the dorsocervical area and abdomen before and after the 4-week intervention.

Undergo analysis of these samples using advanced techniques to understand the presence and activity of brown and beige fat cells.

Comparison Group: Researchers will compare the effects of different interventions (thermoneutral exposure, cold exposure, aerobic exercise, Beta-2 agonist treatment) on the presence and thermogenesis of brown and beige fat cells in the dorsocervical area.

**Detailed Description:** Cardiometabolic diseases affect almost 50% of the population in the Western World. While lifestyle plus pharmacological interventions may provide short-term benefits, more research is needed to understand the long-term effectiveness and underlying molecular mechanisms. Brown adipose tissue (BAT) is a thermogenic tissue that combusts large amounts of glucose and lipids to generate heat and secretes signalling molecules known as 'batokines' that can influence cardiometabolic health. Previous research has shown that BAT is active in adults, primarily in the supraclavicular region, as demonstrated by the uptake of 18F-Fluorodeoxyglucose. Recently, it has been demonstrated that a rare subpopulation of brown adipocytes increases their abundance at higher temperatures and can regulate the thermogenesis of neighbouring adipocytes. Thus, it is plausible that classical (e.g., cold exposure) and novel interventions (i.e., Beta-2 stimulation and exercise) that can activate BAT, would induce a remodelling in the brown/beige subpopulation adipocytes that govern whole tissue thermogenesis. These unstudied changes in human BAT physiology could potentially explain how BAT activation could enhance cardiometabolic health. However, despite over a decade of research, our understanding of the role of BAT in human physiology in humans is limited. This lack of knowledge may be mainly explained because i) obtaining biological samples of human BAT is very difficult and ii) the seasonal variation strongly influences the current gold standard (PET-CT scan). Given the pilot data found in this proposal, young, lean adult women may have a novel and undescribed thermogenic active BAT depot at the dorsocervical area (i.e., interscapular BAT=iBAT).

Based on that, the main hypothesis is that there are brown and/or beige adipocytes present within the subcutaneous adipose tissue of the dorsocervical area (i.e., iBAT) that have a unique composition of adipocyte subpopulations and specific secretory functions. Additionally, the specific subpopulations of brown and/or beige adipocytes related to thermogenesis in iBAT can be increased through exposure to cold temperatures, Beta-2 agonist stimulation, and exercise in young, lean women.

Thus, the main objective of this study is to investigate whether the subcutaneous fat in the dorsocervical area contains active brown and/or beige adipocytes (i.e., iBAT), understand its secretory function, and study the impact of traditional (e.g. cold exposure) and new interventions (e.g. Beta-2 agonist and exercise) on iBAT thermogenesis at the cellular and molecular levels.

Thus, the DEBATE project will carry out a randomized controlled trial where 40 young, lean adult women will be randomized into a thermoneutral exposure group (2 hours/day at 32ºC; 5 days/week) or a cold exposure group (2 hours/day at 18ºC; 5 days/week) or an aerobic exercise group (5 days/week at 65% heart rate reserve for 60 minutes) or a Beta-2 agonist group (salbutamol 12 mg/day. 7 days week). Before and after the 4-week intervention, iBAT tissue samples from the dorsocervical area and subcutaneous white adipose tissue (scWAT) from the abdomen will be collected. In these biological samples, the investigators will apply a set of cutting-edge omics (e.g., single nucleus RNA-seq) that will allow us to investigate whether iBAT is present and metabolically active in adults. The investigators will also conduct a set of in vitro experiments to discover the secretory function of this novel depot.

### Conditions Module

**Conditions:**

- Cardiometabolic Diseases

**Keywords:**

- brown adipose tissue

- cold exposure

- hot exposure

- dorsocervical fat

- exercise

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

**Intervention Model Description:** This study will consist of a randomized controlled trial in which forty young, lean women will be assigned to a control group (n=10; receiving a thermoneutral exposure 2 hours/day at 32ºC; 5 days/week) or a cold exposure group (n=10; receiving 2 hours/day at 18ºC; 5 days/week) or aerobic exercise group (n=10; receiving 5 days/week at 65% heart rate reserve for 60 minutes each training session) or an ADBR2 agonist ingestion (n=10; salbutamol 12 mg/day. 7 days week).

##### Masking Info

**Masking:** SINGLE

**Who Masked:**

- INVESTIGATOR

**Primary Purpose:** BASIC_SCIENCE

#### Enrollment Info

**Count:** 40

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** n=10; receiving a thermoneutral exposure 2 hours/day at 32ºC; 5 days/week; Total 4 weeks

**Intervention Names:**

- Behavioral: Thermoneutral condition

**Label:** Thermoneutral condition

**Type:** PLACEBO_COMPARATOR

#### Arm Group 2

**Description:** n=10; receiving 2 hours/day at 18ºC; 5 days/week; Total 4 weeks

**Intervention Names:**

- Behavioral: Cold condition

**Label:** Cold condition

**Type:** EXPERIMENTAL

#### Arm Group 3

**Description:** n=10; salbutamol 12 mg/day. 7 days week. Total 4 weeks

**Intervention Names:**

- Drug: Salbutamol

**Label:** Salbutamol

**Type:** EXPERIMENTAL

#### Arm Group 4

**Description:** n=10; receiving 5 days/week at 65% heart rate reserve for 60 minutes each training session. Total 4 weeks

**Intervention Names:**

- Behavioral: Aerobic exercise condition

**Label:** Aerobic exercise

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Thermoneutral condition

**Description:** Participants will be exposed 2 hours/day at 32ºC for 5 days/week

**Name:** Thermoneutral condition

**Type:** BEHAVIORAL

#### Intervention 2

**Arm Group Labels:**

- Cold condition

**Description:** Participants will be exposed 2 hours/day at 18ºC for 5 days/week

**Name:** Cold condition

**Type:** BEHAVIORAL

#### Intervention 3

**Arm Group Labels:**

- Aerobic exercise

**Description:** Participants will perform aerobic exercise training 5 days/week at 65% heart rate reserve for 60 minutes each training session

**Name:** Aerobic exercise condition

**Type:** BEHAVIORAL

#### Intervention 4

**Arm Group Labels:**

- Salbutamol

**Description:** Participants will take salbutamol 12 mg/day. 7 days week

**Name:** Salbutamol

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Investigators will quantify the level UCP1 expression by qPCR in white adipose tissue biopsies obtained before and after the intervention

**Measure:** Change in UCP1 expression in the dorsocervical area

**Time Frame:** 2 years

#### Secondary Outcomes

**Description:** Change in fat percentage (% of fat)

**Measure:** Body composition (BIA, Tanita)

**Time Frame:** 2 years

**Description:** Change in VO2max (ml/kg/min)

**Measure:** Cardiorespiratory fitness test (indirect calorimetry and monarch bike)

**Time Frame:** 2 years

**Description:** Change in LDL-C (mg/dL)

**Measure:** LDL quantification in blood

**Time Frame:** 2 years

**Description:** Change in HDL-C (mg/dL)

**Measure:** HDL quantification in blood

**Time Frame:** 2 years

**Description:** Change in Glucose (mg/dL)

**Measure:** Glucose quantification in blood

**Time Frame:** 2 years

**Description:** Change in Insulin (µIU/mL)

**Measure:** Insulin quantification in blood

**Time Frame:** 2 years

**Description:** Change in Triglycerides (mg/dL)

**Measure:** Triglycerides quantification in blood

**Time Frame:** 2 years

**Description:** Change in CRP (mg/L)

**Measure:** C-reactive protein quantification in blood

**Time Frame:** 2 years

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* 18-22 years of age women.
* BMI between ≥18 and \<25 kg/m2
* Are willing to be randomized to either of these 4 groups.
* Must be sedentary (i.e., do not perform exercise or go to the gym).
* Participants should have regular menstrual cycles.
* Must be willing to adhere to all study procedures, including attendance at all study visits.
* Must be willing to have biological samples stored for future research.
* Must accept the use of the Period Calendar and Google Fit Apps on their mobile phones.

Exclusion Criteria:

* Diabetes mellitus (determined based on fasting glucose levels defined by ADA criteria).
* Any other active endocrine disease (thyroid disease, any signs of Cushing's syndrome, adrenal disease and lipid-associated disorders such as familial hypercholesterolemia).
* Any cardiac disease (i.e., ischemic cardiac disease, arrhythmias, severe heart failure).
* Use of medication known to influence glucose and/or lipid metabolism or brown fat activity (e.g., beta-blockers, antidepressants, corticosteroids).
* Use of medication shown to increase risk of hypokalemia after salbutamol administration (e.g., xanthine derivatives, steroids and diuretics).
* Clinically relevant abnormalities in clinical chemistry or electrocardiogram (ECG) at screening (to be judged by the study physician).
* A first-degree family member with sudden cardiac death.
* Any chronic renal or hepatic disease.
* Any other contra-indications for the use of salbutamol or propranolol.
* Abuse of alcohol or other substances.
* Smoking.
* Current participation in another research projects that may influence the current research project.
* Use of beta-adrenergic receptor agonists (e.g., asthma).
* Polycystic ovary syndrome.
* Diagnosed psychotic conditions.

**Healthy Volunteers:** True

**Maximum Age:** 22 Years

**Minimum Age:** 18 Years

**Sex:** FEMALE

**Standard Ages:**

- ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** borjammt@ual.es

**Name:** Borja Martinez Tellez, PhD

**Phone:** +34 950215334

**Phone Ext:** +34

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Almería

**Country:** Spain

**Facility:** Universidad de Almería

**Zip:** 04131

### IPD Sharing Statement Module

**Access Criteria:** Everybody

**Info Types:**

- STUDY_PROTOCOL

- ICF

- CSR

**IPD Sharing:** YES

**Time Frame:** 5 years after publishing the data

**URL:** https://www.sportresearchgroup.es/

### References Module

#### References

**Citation:** Martinez-Tellez B, Sanchez-Delgado G, Alcantara JMA, Acosta FM, Amaro-Gahete FJ, Osuna-Prieto FJ, Perez-Bey A, Jimenez-Pavon D, Llamas-Elvira JM, Gil A, Aguilera CM, Rensen PCN, Ruiz JR. Evidence of high 18 F-fluorodeoxyglucose uptake in the subcutaneous adipose tissue of the dorsocervical area in young adults. Exp Physiol. 2019 Feb;104(2):168-173. doi: 10.1113/EP087428. Epub 2018 Dec 18.

**PMID:** 30468689

## Derived Section

### Condition Browse Module - Browse Branches

- Abbrev: BC01

- Name: Infections

- Abbrev: BC08

- Name: Respiratory Tract (Lung and Bronchial) Diseases

- Abbrev: All

- Name: All Conditions

### Condition Browse Module - Browse Leaves

- ID: M14978

- Name: Respiratory Tract Infections

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Ancestors

- ID: D000001993

- Term: Bronchodilator Agents

- ID: D000001337

- Term: Autonomic Agents

- ID: D000018373

- Term: Peripheral Nervous System Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000018927

- Term: Anti-Asthmatic Agents

- ID: D000019141

- Term: Respiratory System Agents

- ID: D000015149

- Term: Tocolytic Agents

- ID: D000012102

- Term: Reproductive Control Agents

- ID: D000058666

- Term: Adrenergic beta-2 Receptor Agonists

- ID: D000000318

- Term: Adrenergic beta-Agonists

- ID: D000000322

- Term: Adrenergic Agonists

- ID: D000018663

- Term: Adrenergic Agents

- ID: D000018377

- Term: Neurotransmitter Agents

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

### Intervention Browse Module - Browse Branches

- Abbrev: Repr

- Name: Reproductive Control Agents

- Abbrev: Resp

- Name: Respiratory System Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M3767

- Name: Albuterol

- Relevance: HIGH

- As Found: Residual

- ID: M5269

- Name: Bronchodilator Agents

- Relevance: LOW

- As Found: Unknown

- ID: M20963

- Name: Anti-Asthmatic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M21137

- Name: Respiratory System Agents

- Relevance: LOW

- As Found: Unknown

- ID: M17869

- Name: Tocolytic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M20746

- Name: Adrenergic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M3670

- Name: Adrenergic beta-Agonists

- Relevance: LOW

- As Found: Unknown

- ID: M3673

- Name: Adrenergic Agonists

- Relevance: LOW

- As Found: Unknown

- ID: M20504

- Name: Neurotransmitter Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000000420

- Term: Albuterol

### Misc Info Module

- Version Holder: 2024-05-31
