Pharmacological Activation of Brown Adipose Tissue Metabolism

The first step of the study will be direct comparison of mirabegron (protocol A) vs. cold-induced (protocol B) BAT metabolic activation using 11C-acetate to measure BAT metabolic activity. The principle of this method is measurement of tissue fast disappearance of 11C, a marker of tissue 11CO2 production. This fast tissue 11C clearance thus gives an index of tissue oxidative metabolism. Ten healthy, non obese men will undergo two identical 5h procedures in which BAT metabolism will be stimulated with a β3-agonist (mirabegron 50mg) or using cold exposure, in random order. The investigator just received approval from Health Canada to use mirabegron as part of these metabolic investigations. In brief, baseline blood samples and indirect calorimetry will be performed between time -60 to -30 min followed by i.v. injection of 11C-acetate with 30 min dynamic PET/CT scanning at room temperature in both protocol A and B. Mirabegron will be administered orally at time 0 in protocol A whereas acute cold exposure protocol using a water-conditioned cooling suit will be applied from time 120 to 300 min in protocol B. At time 210 min (i.e. Tmax of plasma mirabegron level or 90 min after the onset of cold exposure), i.v. injection of 11C-acetate will be repeated followed by 30 min dynamic PET/CT scanning. I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed at time 270 min, followed by 30 min dynamic PET/CT scanning to determine BAT net glucose uptake and a whole-body PET/CT scan to determine BAT volume of metabolic activity and organ-specific glucose partitioning.

Inclusion criteria

• BMI < 30 kg/m2
• normal glucose tolerance (2-hour post 75g OGTT glucose at < 7.8 mmol/l
• HbA1c < 5.8%

Exclusion criteria

• overt cardiovascular disease as assessed by medical history, physical exam, and abnormal ECG;
• treatment with any drug known to affect lipid or carbohydrate metabolism;
• presence of liver or renal disease, uncontrolled thyroid disorder, previous pancreatitis, bleeding disorder, or other major illness;
• smoking (>1 cigarette/day) and/or consumption of >2 alcoholic beverages per day;
• prior history or current fasting plasma cholesterol level > 7 mmol/l or fasting TG > 6 mmol/l.