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

Université de Sherbrooke12 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Interventions

Formoterol Fumarate 12 micrograms Inhalation PowderDRUG

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 TabletDRUG

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.

Acute Cold ExposureOTHER

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.

Positron Emission Tomography (PET)DIAGNOSTIC_TEST

PET imaging using C11-palmitate (time 90), C11-acetate (time 120) and F18-Fluorodeoxyglucose (FDG) (time 150)

Indirect calorimetryDIAGNOSTIC_TEST

will be repeated every hour, for 20 minutes, using Vmax29n.

dual-energy x-ray absorptiometry (DEXA scan)DIAGNOSTIC_TEST

Whole body scan

BiopsyPROCEDURE

After local anesthesia with 2% xylocaine without epinephrine, 100-200 mg of subcutaneous adipose tissue will be sampled by needle (14G) biopsy

iv linesPROCEDURE

for stable tracer perfusion and blood sampling

Electromyogram (EMG)PROCEDURE

Surface electrodes will be used to measure skeletal muscle activity and shivering intensity

Eligibility

Sex: ALLMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Change in Brown Adipose Tissue thermogenesis (formoterol induced, cold-induced and effect of nicotinic acid)

determined using \[11C\]-acetate PET

Time frame: measured 60 minutes before and 90 minutes after cold exposure (A) and 30 minutes after inhalation of Fumarate Formoterol (B and C)

Secondary Outcomes

Brown Adipose Tissue (BAT) glucose uptake

determined using \[18F\]-FDG dynamic PET acquisition

Time frame: 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

Time frame: 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.

Time frame: 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 .

Time frame: 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 .

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: 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)