Activation of Brown Adipose Tissue Thermogenesis in Humans Using Formoterol Fumarate, a Beta-2 Adrenergic Receptor Agonist
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Change in Brown Adipose Tissue thermogenesis (formoterol induced, cold-induced and effect of nicotinic acid)
研究概览
简要总结
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.
详细描述
Each participant will undergo three metabolic sessions with PET imaging using [11C]-palmitate, [11C]-acetate and [18F]-FDG:
- during a 3-h cold exposure (Study A, control condition)
- after inhalation of Formoterol with oral nicotinic acid (Study B)
- after inhalation of Formoterol only (Study C).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •BMI of 18 to 30 kg/m2.
排除标准
- •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.
研究组 & 干预措施
Acute Cold Exposure
3h-acute cold exposure.
干预措施: dual-energy x-ray absorptiometry (DEXA scan) (Diagnostic Test)
Acute Cold Exposure
3h-acute cold exposure.
干预措施: Acute Cold Exposure (Other)
Acute Cold Exposure
3h-acute cold exposure.
干预措施: Positron Emission Tomography (PET) (Diagnostic Test)
Acute Cold Exposure
3h-acute cold exposure.
干预措施: Indirect calorimetry (Diagnostic Test)
Acute Cold Exposure
3h-acute cold exposure.
干预措施: Biopsy (Procedure)
Acute Cold Exposure
3h-acute cold exposure.
干预措施: iv lines (Procedure)
Acute Cold Exposure
3h-acute cold exposure.
干预措施: Electromyogram (EMG) (Procedure)
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.
干预措施: Formoterol Fumarate 12 micrograms Inhalation Powder (Drug)
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.
干预措施: Nicotinic Acid 50 MG Oral Tablet (Drug)
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.
干预措施: Positron Emission Tomography (PET) (Diagnostic Test)
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.
干预措施: Indirect calorimetry (Diagnostic Test)
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.
干预措施: Biopsy (Procedure)
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.
干预措施: iv lines (Procedure)
Formoterol without nicotinic acid
Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg).
干预措施: Formoterol Fumarate 12 micrograms Inhalation Powder (Drug)
Formoterol without nicotinic acid
Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg).
干预措施: Positron Emission Tomography (PET) (Diagnostic Test)
Formoterol without nicotinic acid
Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg).
干预措施: Indirect calorimetry (Diagnostic Test)
Formoterol without nicotinic acid
Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg).
干预措施: Biopsy (Procedure)
Formoterol without nicotinic acid
Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg).
干预措施: iv lines (Procedure)
结局指标
主要结局
Change in Brown Adipose Tissue thermogenesis (formoterol induced, cold-induced and effect of nicotinic acid)
时间窗: measured 60 minutes before and 90 minutes after cold exposure (A) and 30 minutes after inhalation of Fumarate Formoterol (B and C)
determined using \[11C\]-acetate PET
次要结局
- Brown Adipose Tissue (BAT) glucose uptake(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)(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.(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 glucose turnover.(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(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(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(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(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(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))
- Change in systemic plasma glycerol turnover.(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.)
研究者
André Carpentier
Tenure professor
Université de Sherbrooke