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Completed

NCT Number: NCT05553184

Activation of Brown Adipose Tissue Thermogenesis in Humans Using Formoterol Fumarate (GB10)

One emerging, highly modifiable homeostatic mechanism for energy expenditure in humans is brown adipose tissue (BAT) thermogenesis. BAT is currently considered a prime target for the treatment of obesity and Type 2 diabetes (T2D).

Using acetate and fluorodeoxyglucose (FDG) positron emission tomography (PET) , It has been demonstrated that BAT thermogenesis is inducible by chronic cold exposure.

BAT activation through cold exposure is associated with improved glucose homeostasis and insulin sensitivity.

A pharmaceutical approach, which seemed to be very promising to stimulate the activation of BAT, was the use of a selective beta 3-adrenergic receptor agonist, mirabegron. Nevertheless, in a later study, It has been demonstrated that human BAT thermogenesis is under the control of beta-2, not beta-3, adrenergic receptor. The most selective beta-2 adrenergic receptor agonist approved for clinical use in Canada is formoterol fumarate, given in inhalation for the treatment of asthma (Oxeze®).

In summary, BAT contributes to cold-induced thermogenesis and is recruited by chronic cold exposure as well as by a growing number of food supplements and drugs. Intracellular triglyceride (TG) is the primary source of fuel for BAT thermogenesis under normal physiological conditions, as blocking intracellular TG lipolysis using nicotinic acid abolishes BAT thermogenesis. Beta-2 adrenergic stimulation is the pharmacological target to activate BAT thermogenesis in humans and may also lead to white adipose tissue lipolysis. Using a highly-selective beta-2 receptor agonist with and without administration of nicotinic acid would thus give the opportunity to quantify more precisely energy expenditure accounted by BAT thermogenesis and white adipose tissue metabolism in humans.

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Key information

Conditions

Type 2 Diabetes Body Weight Diabetes Mellitus Diabetes Mellitus, Type 2 Endocrine System Diseases Glucose Metabolism Disorders Metabolic Diseases Nutrition Disorders Nutritional and Metabolic Diseases Obesity Overnutrition Overweight Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

18 year–45 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Centre de recherche du CHUS

Sherbrooke, Quebec, J1H 5N4, Canada

About this study

Each participant will undergo three metabolic sessions with PET imaging using [11C]-palmitate, [11C]-acetate and [18F]-FDG:

  • during a 3-h cold exposure (Study A, control condition)
  • after inhalation of Formoterol with oral nicotinic acid (Study B)
  • after inhalation of Formoterol only (Study C).

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • BMI of 18 to 30 kg/m2.

Exclusion criteria

  • Change in weight of more than 2 kg over the past 3 months or recent changes in lifestyle;
  • The presence of any chronic medical condition requiring any pharmacological treatment;
  • Previous intolerance or allergy to lactose, formoterol, nicotinic acid or local anesthetic agent;
  • Any previous cardiac arrhythmia, long QT syndrome or hypokalemia;
  • Chronic treatment with any medication other than contraceptives;
  • Acute use of any drug other that acetaminophen or non-steroidal anti-inflammatory without decongestant or other stimulants;
  • Smoking or consumption of more than 2 alcoholic beverages per day;
  • Having participated to a research study with exposure to radiation in the last two years before the start of the study.

Treatment and study plan

Formoterol Fumarate 12 micrograms Inhalation Powder

Drug

At time 60 minutes, a total of 48 micrograms will be inhaled within 3 minutes: 4 inhalations of 12 micrograms of fumarate formoterol (Oxeze® Turbuhaler®).

Other names: Oxeze Turbuhaler

Nicotinic Acid 50 MG Oral Tablet

Drug

a total dose of 1050 MG will be ingested. From time 0 to 180 minutes, doses of 150 MG will be repeated every 30 minutes.

Other names: Niacin 50 MG

Acute cold exposure

Other

Participants will be fitted with a liquid-conditioned tube suit. The liquid-conditioned tube suit will be perfused with 18°C water using a temperature- and flow-controlled circulation bath from time 0 to 180 min.

Positron Emission Tomography (PET)

Diagnostic Test

PET imaging using C11-palmitate (time 90), C11-acetate (time 120) and F18-Fluorodeoxyglucose (FDG) (time 150)

indirect calorimetry

Diagnostic Test

will be repeated every hour, for 20 minutes, using Vmax29n.

Dual-energy X-ray absorptiometry (DEXA scan)

Diagnostic Test

Whole body scan

Biopsy

Procedure

After local anesthesia with 2% xylocaine without epinephrine, 100-200 mg of subcutaneous adipose tissue will be sampled by needle (14G) biopsy

iv lines

Procedure

for stable tracer perfusion and blood sampling

Electromyogram (EMG)

Procedure

Surface electrodes will be used to measure skeletal muscle activity and shivering intensity

Primary outcomes

  1. Change in Brown Adipose Tissue thermogenesis (formoterol induced, cold-induced and effect of nicotinic acid)

    Time frame: measured 60 minutes before and 90 minutes after cold exposure (A) and 30 minutes after inhalation of Fumarate Formoterol (B and C)

    determined using [11C]-acetate PET

Secondary outcomes

  1. Brown Adipose Tissue (BAT) glucose uptake

    Time frame: measured 150 minutes after the start of acute cold exposure (A), and 90 minutes after inhalation of Fumarate Formoterol (B and C)

    determined using [18F]-FDG dynamic PET acquisition

  2. Brown Adipose Tissue nonesterified fatty acid (NEFA) metabolism (uptake, oxidation, esterification and release rates)

    Time frame: measured 120 minutes after the start of acute cold exposure (A), and 60 minutes after inhalation of Fumarate Formoterol (B and C)

    determined using [11C]-palmitate PET method

  3. Change in systemic plasma NEFA turnover.

    Time frame: measured at baseline and every 60 minutes after the start of acute cold exposure (A) and every 60 minutes after inhalation of fumarate formoterol (B and C), for 4 hours

    Determined using continuous infusion of labelled palmitate from time -60 to 180.

  4. Change in systemic plasma glycerol turnover.

    Time frame: measured at baseline and every hour after the start of acute cold exposure (A) and every hour after inhalation of fumarate formoterol (B and C), for 4 hours.

    Determined using continuous infusion of [1,1,2,3,3-D2]-glycerol from time -60 to 180 .

  5. Change in systemic plasma glucose turnover.

    Time frame: measured at baseline and every hour after the start of acute cold exposure (A) and every hour after inhalation of fumarate formoterol (B and C), for 5.50 hours

    Determined using continuous infusion of [6,6 D2]-glucose from time -150 to 180 .

  6. BAT triglyceride content

    Time frame: measured 180 minutes after the start of cold exposure (A) and 90 minutes after inhalation of fumarate formoterol (B and C)

    Determined using the CT radio-density method

  7. Change in whole-body energy expenditure

    Time frame: measured at baseline and every hour after the start of acute cold exposure (A) and every hour after inhalation of fumarate formoterol (B and C), for 4 hours

    Determined using indirect calorimetry

  8. Muscle shivering activity

    Time frame: measured at baseline and every hour after the start of acute cold exposure (A) and every hour after inhalation of fumarate formoterol (B and C), for 4 hours

    Determined using the surface electromyogram (EMG)

  9. Change in insulin sensitivity

    Time frame: measured at baseline and every 60 minutes after the start of acute cold exposure (A) and every 60 minutes after inhalation of fumarate formoterol (B and C), for 4 hours.

    Determined by measuring circulating glucose, NEFA, insulin and C-peptide

  10. Protein expression of subcutaneous abdominal white adipose tissue

    Time frame: measured at baseline and 180 minutes after the start of the cold exposure (study A) and 120 minutes after inhalation of fumarate formoterol (study B and C)

    Using biopsy

Sponsors and collaborators

Lead sponsor

Université de Sherbrooke

Other

Registry information

Official study title

Activation of Brown Adipose Tissue Thermogenesis in Humans Using Formoterol Fumarate, a Beta-2 Adrenergic Receptor Agonist

Acronym: GB10

Important dates

Study start
2022
Primary completion
2023
Study completion
2023
First posted
Sep 23, 2022
Registry last updated
Nov 28, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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