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

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.

Conditions

• Type 2 Diabetes
• Obesity

Interventions

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®).

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

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

Sponsors & Collaborators

• Université de Sherbrooke

  lead OTHER

Principal Investigators

• André C. Carpentier, M.D. · Université de Sherbrooke

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

45 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2022-07-05

Primary Completion

2023-05-29

Completion

2023-05-29

Countries

• Canada

Study Locations