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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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Obesity, Type 2 Diabetes

Intervention / Treatment
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* Drug: Formoterol Fumarate 12 micrograms Inhalation Powder
* Drug: Nicotinic Acid 50 MG Oral Tablet
* Other: Acute Cold Exposure
* Diagnostic Test: Positron Emission Tomography (PET)
* Diagnostic Test: Indirect calorimetry
* Diagnostic Test: dual-energy x-ray absorptiometry (DEXA scan)
* Procedure: Biopsy
* Procedure: iv lines
* Procedure: Electromyogram (EMG)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The protocol will be carried out as a within-subject, randomized, cross-over study in which each subject will serve as his/her own control
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Acute Cold Exposure<br>3h-acute cold exposure. | Other: Acute Cold Exposure<br>* 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.<br>Diagnostic Test: Positron Emission Tomography (PET)<br>* PET imaging using C11-palmitate (time 90), C11-acetate (time 120) and F18-Fluorodeoxyglucose (FDG) (time 150)<br>Diagnostic Test: Indirect calorimetry<br>* will be repeated every hour, for 20 minutes, using Vmax29n.<br>Diagnostic Test: dual-energy x-ray absorptiometry (DEXA scan)<br>* Whole body scan<br>Procedure: Biopsy<br>* After local anesthesia with 2% xylocaine without epinephrine, 100-200 mg of subcutaneous adipose tissue will be sampled by needle (14G) biopsy<br>Procedure: iv lines<br>* for stable tracer perfusion and blood sampling<br>Procedure: Electromyogram (EMG)<br>* Surface electrodes will be used to measure skeletal muscle activity and shivering intensity<br>|
| Experimental: Formoterol with nicotinic acid<br>Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg). Nicotinic acid or Niacin: repeated doses of 150 MG every 30 minutes, for 3 hours. | Drug: Formoterol Fumarate 12 micrograms Inhalation Powder<br>* 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®).<br>* Other names: Oxeze Turbuhaler;Drug: Nicotinic Acid 50 MG Oral Tablet<br>* 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.<br>* Other names: Niacin 50 MG;Diagnostic Test: Positron Emission Tomography (PET)<br>* PET imaging using C11-palmitate (time 90), C11-acetate (time 120) and F18-Fluorodeoxyglucose (FDG) (time 150)<br>Diagnostic Test: Indirect calorimetry<br>* will be repeated every hour, for 20 minutes, using Vmax29n.<br>Procedure: Biopsy<br>* After local anesthesia with 2% xylocaine without epinephrine, 100-200 mg of subcutaneous adipose tissue will be sampled by needle (14G) biopsy<br>Procedure: iv lines<br>* for stable tracer perfusion and blood sampling<br>|
| Experimental: Formoterol without nicotinic acid<br>Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg). | Drug: Formoterol Fumarate 12 micrograms Inhalation Powder<br>* 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®).<br>* Other names: Oxeze Turbuhaler;Diagnostic Test: Positron Emission Tomography (PET)<br>* PET imaging using C11-palmitate (time 90), C11-acetate (time 120) and F18-Fluorodeoxyglucose (FDG) (time 150)<br>Diagnostic Test: Indirect calorimetry<br>* will be repeated every hour, for 20 minutes, using Vmax29n.<br>Procedure: Biopsy<br>* After local anesthesia with 2% xylocaine without epinephrine, 100-200 mg of subcutaneous adipose tissue will be sampled by needle (14G) biopsy<br>Procedure: iv lines<br>* for stable tracer perfusion and blood sampling<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Brown Adipose Tissue thermogenesis (formoterol induced, cold-induced and effect of nicotinic acid) | determined using [11C]-acetate PET | measured 60 minutes before and 90 minutes after cold exposure (A) and 30 minutes after inhalation of Fumarate Formoterol (B and C) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brown Adipose Tissue (BAT) glucose uptake | determined using [18F]-FDG dynamic PET acquisition | measured 150 minutes after the start of acute cold exposure (A), and 90 minutes after inhalation of Fumarate Formoterol (B and C) | 
| Brown Adipose Tissue nonesterified fatty acid (NEFA) metabolism (uptake, oxidation, esterification and release rates) | determined using [11C]-palmitate PET method | measured 120 minutes after the start of acute cold exposure (A), and 60 minutes after inhalation of Fumarate Formoterol (B and C) | 
| Change in systemic plasma NEFA turnover. | Determined using continuous infusion of labelled palmitate from time -60 to 180. | 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 | 
| Change in systemic plasma glycerol turnover. | Determined using continuous infusion of [1,1,2,3,3-D2]-glycerol from time -60 to 180 . | 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. | 
| Change in systemic plasma glucose turnover. | Determined using continuous infusion of [6,6 D2]-glucose from time -150 to 180 . | 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 | 
| BAT triglyceride content | Determined using the CT radio-density method | measured 180 minutes after the start of cold exposure (A) and 90 minutes after inhalation of fumarate formoterol (B and C) | 
| Change in whole-body energy expenditure | Determined using indirect calorimetry | 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 | 
| Muscle shivering activity | Determined using the surface electromyogram (EMG) | 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 | 
| Change in insulin sensitivity | Determined by measuring circulating glucose, NEFA, insulin and C-peptide | 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. | 
| Protein expression of subcutaneous abdominal white adipose tissue | Using biopsy | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brown adipose tissue, formoterol fumarate, Thermogenesis