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

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).

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.