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

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

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Type 2 Diabetes
• Intervention / Treatment: 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); Drug: Formoterol Fumarate 12 micrograms Inhalation Powder; Drug: Nicotinic Acid 50 MG Oral Tablet

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).

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Frédérique Frisch; Phone Number: 8195883842; Email: frederiquefrisch@gmail.com

Study Locations

• Canada
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre de recherche du CHUS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 43 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Acute Cold Exposure; 3h-acute cold exposure.	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); Diagnostic test: Indirect calorimetry; will be repeated every hour, for 20 minutes, using Vmax29n.; Diagnostic test: 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; Procedure: iv lines; for stable tracer perfusion and blood sampling; Procedure: Electromyogram (EMG); Surface electrodes will be used to measure skeletal muscle activity and shivering intensity
Experimental: Formoterol with nicotinic acid; 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.	Diagnostic test: Positron Emission Tomography (PET); PET imaging using C11-palmitate (time 90), C11-acetate (time 120) and F18-Fluorodeoxyglucose (FDG) (time 150); Diagnostic test: Indirect calorimetry; will be repeated every hour, for 20 minutes, using Vmax29n.; Procedure: Biopsy; After local anesthesia with 2% xylocaine without epinephrine, 100-200 mg of subcutaneous adipose tissue will be sampled by needle (14G) biopsy; Procedure: iv lines; for stable tracer perfusion and blood sampling; 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®).; Other Names: Oxeze Turbuhaler; Drug: 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 Names: Niacin 50 MG
Experimental: Formoterol without nicotinic acid; Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg).	Diagnostic test: Positron Emission Tomography (PET); PET imaging using C11-palmitate (time 90), C11-acetate (time 120) and F18-Fluorodeoxyglucose (FDG) (time 150); Diagnostic test: Indirect calorimetry; will be repeated every hour, for 20 minutes, using Vmax29n.; Procedure: Biopsy; After local anesthesia with 2% xylocaine without epinephrine, 100-200 mg of subcutaneous adipose tissue will be sampled by needle (14G) biopsy; Procedure: iv lines; for stable tracer perfusion and blood sampling; 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®).; Other Names: Oxeze Turbuhaler

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Université de Sherbrooke
• Investigators: Principal Investigator: André C. Carpentier, M.D., Université de Sherbrooke

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2022
• Primary Completion (Actual): May 29, 2023
• Study Completion (Actual): May 29, 2023

Study Registration Dates

• First Submitted: August 25, 2022
• First Submitted That Met QC Criteria: September 22, 2022
• First Posted (Actual): September 23, 2022

Study Record Updates

• Last Update Posted (Actual): November 28, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Brown adipose tissue; formoterol fumarate; Thermogenesis
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Antimetabolites; Adrenergic Agonists; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Vitamins; Vitamin B Complex; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Nicotinic Acids; Niacinamide; Niacin; Formoterol Fumarate
• Other Study ID Numbers: GB10-2021-3873

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No