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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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Acute Cold Exposure | Active Comparator | 3h-acute cold exposure. |
|
| Formoterol with nicotinic acid | Experimental | 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. |
|
| Formoterol without nicotinic acid | Experimental | Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Formoterol Fumarate 12 micrograms Inhalation Powder | Drug | 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®). |
| 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) |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| André C. Carpentier, M.D. | Université de Sherbrooke | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centre de recherche du CHUS | Sherbrooke | Quebec | J1H 5N4 | Canada |
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The protocol will be carried out as a within-subject, randomized, cross-over study in which each subject will serve as his/her own control
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|
| Nicotinic Acid 50 MG Oral Tablet | Drug | 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 Exposure | Other | 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 calorimetry | Diagnostic Test | will be repeated every hour, for 20 minutes, using Vmax29n. |
|
| dual-energy x-ray absorptiometry (DEXA scan) | Diagnostic Test | Whole body scan |
|
| Biopsy | Procedure | After local anesthesia with 2% xylocaine without epinephrine, 100-200 mg of subcutaneous adipose tissue will be sampled by needle (14G) biopsy |
|
| iv lines | Procedure | for stable tracer perfusion and blood sampling |
|
| Electromyogram (EMG) | Procedure | Surface electrodes will be used to measure skeletal muscle activity and shivering intensity |
|
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) |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D009765 | Obesity |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D009525 | Niacin |
| D013607 | Tablets |
| D049268 | Positron-Emission Tomography |
| D015502 | Absorptiometry, Photon |
| D001706 | Biopsy |
| ID | Term |
|---|---|
| D009539 | Nicotinic Acids |
| D000147 | Acids, Heterocyclic |
| D006571 | Heterocyclic Compounds |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
| D014055 | Tomography, Emission-Computed |
| D007090 | Image Interpretation, Computer-Assisted |
| D003952 | Diagnostic Imaging |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D007089 | Image Enhancement |
| D010781 | Photography |
| D011877 | Radionuclide Imaging |
| D014054 | Tomography |
| D003947 | Diagnostic Techniques, Radioisotope |
| D011859 | Radiography |
| D003720 | Densitometry |
| D010783 | Photometry |
| D002623 | Chemistry Techniques, Analytical |
| D008919 | Investigative Techniques |
| D003581 | Cytodiagnosis |
| D003584 | Cytological Techniques |
| D019411 | Clinical Laboratory Techniques |
| D013048 | Specimen Handling |
| D003949 | Diagnostic Techniques, Surgical |
| D013514 | Surgical Procedures, Operative |
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