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

Obesity Clinical Trial

— GB10  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05553184
• Other study ID #: GB10-2021-3873
• Status: Completed
• Phase: N/A
• Start date: July 5, 2022
• Est. completion date: May 29, 2023

Study information

• Verified date: November 2023
• Source: Université de Sherbrooke
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: May 29, 2023
• Est. primary completion date: May 29, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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.

Related Conditions & MeSH terms

• Obesity
• Type 2 Diabetes

Intervention

Drug:
• Formoterol Fumarate 12 micrograms Inhalation Powder
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®).
• Nicotinic Acid 50 MG Oral Tablet
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:
• Acute Cold Exposure
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.

Diagnostic Test:
• Positron Emission Tomography (PET)
PET imaging using C11-palmitate (time 90), C11-acetate (time 120) and F18-Fluorodeoxyglucose (FDG) (time 150)
• Indirect calorimetry
will be repeated every hour, for 20 minutes, using Vmax29n.
• dual-energy x-ray absorptiometry (DEXA scan)
Whole body scan

Procedure:
• Biopsy
After local anesthesia with 2% xylocaine without epinephrine, 100-200 mg of subcutaneous adipose tissue will be sampled by needle (14G) biopsy
• iv lines
for stable tracer perfusion and blood sampling
• Electromyogram (EMG)
Surface electrodes will be used to measure skeletal muscle activity and shivering intensity

Locations

Country	Name	City	State
Canada	Centre de recherche du CHUS	Sherbrooke	Quebec

Sponsors (1)

Lead Sponsor	Collaborator
Université de Sherbrooke

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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
Secondary	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.
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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.
Secondary	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)