Activation of Brown Adipose Tissue Thermogenesis in Humans Using Formoterol Fumarate (GB10)
- Conditions
- ObesityType 2 Diabetes
- Interventions
- Other: Acute Cold ExposureDiagnostic Test: Positron Emission Tomography (PET)Drug: Nicotinic Acid 50 MG Oral TabletDiagnostic Test: Indirect calorimetryDiagnostic Test: dual-energy x-ray absorptiometry (DEXA scan)Procedure: BiopsyProcedure: iv linesProcedure: Electromyogram (EMG)
- Registration Number
- NCT05553184
- Lead Sponsor
- Université de Sherbrooke
- Brief Summary
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
Each participant will undergo three metabolic sessions with PET imaging using \[11C\]-palmitate, \[11C\]-acetate and \[18F\]-FDG:
1. during a 3-h cold exposure (Study A, control condition)
2. after inhalation of Formoterol with oral nicotinic acid (Study B)
3. after inhalation of Formoterol only (Study C).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 12
- BMI of 18 to 30 kg/m2.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Acute Cold Exposure Acute Cold Exposure 3h-acute cold exposure. Acute Cold Exposure Positron Emission Tomography (PET) 3h-acute cold exposure. Acute Cold Exposure Indirect calorimetry 3h-acute cold exposure. Acute Cold Exposure dual-energy x-ray absorptiometry (DEXA scan) 3h-acute cold exposure. Acute Cold Exposure Biopsy 3h-acute cold exposure. Acute Cold Exposure iv lines 3h-acute cold exposure. Acute Cold Exposure Electromyogram (EMG) 3h-acute cold exposure. Formoterol with nicotinic acid Nicotinic Acid 50 MG Oral Tablet 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. Formoterol with nicotinic acid Positron Emission Tomography (PET) 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. Formoterol with nicotinic acid Indirect calorimetry 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. Formoterol with nicotinic acid Biopsy 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. Formoterol with nicotinic acid iv lines 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. Formoterol without nicotinic acid iv lines Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg). Formoterol without nicotinic acid Biopsy Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg). Formoterol without nicotinic acid Formoterol Fumarate 12 micrograms Inhalation Powder Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg). Formoterol without nicotinic acid Positron Emission Tomography (PET) Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg). Formoterol without nicotinic acid Indirect calorimetry Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg). Formoterol with nicotinic acid Formoterol Fumarate 12 micrograms Inhalation Powder 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.
- Primary Outcome Measures
Name Time Method Change in Brown Adipose Tissue thermogenesis (formoterol induced, cold-induced and effect of nicotinic acid) 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 Outcome Measures
Name Time Method Brown Adipose Tissue (BAT) glucose uptake 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
Brown Adipose Tissue nonesterified fatty acid (NEFA) metabolism (uptake, oxidation, esterification and release rates) 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
Change in systemic plasma NEFA turnover. 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.
Change in systemic plasma glucose turnover. 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 .
BAT triglyceride content 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
Change in whole-body energy expenditure 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
Muscle shivering activity 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)
Change in insulin sensitivity 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
Protein expression of subcutaneous abdominal white adipose tissue 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
Change in systemic plasma glycerol turnover. 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 .
Trial Locations
- Locations (1)
Centre de recherche du CHUS
🇨🇦Sherbrooke, Quebec, Canada