Pharmacological Activation of Brown Adipose Tissue Metabolism

• Status: Completed
• Trial end date: 2018-07-05
• Target enrollment: 0
• Participant gender: Male

Summary

Lean tissue intracellular triglycerides (ICTG) accretion is an important marker of lean tissue lipotoxicity that significantly contributes to the development of type 2 diabetes (T2D). The mechanisms leading to excess exposure of lean tissues to fatty acids involve metabolic dysfunctions of adipose tissues and lean tissues themselves. Understanding the role of white and brown adipose tissue in this metabolic dysfunction is particularly important in predicting, preventing and treating T2D and many of its associated cardiovascular complications.

A recent breakthrough has been the demonstration that the acute oral administration of a β3 adrenergic agonist, mirabegron (200 mg), significantly increases BAT glucose uptake in healthy individuals. This suggests that mirabegron could be used as a pharmacological tool to selectively activate BAT metabolism as part of the mechanistic studies on BAT. It also suggests that mirabegron could be used pharmacologically for chronic activation of BAT in clinical trials to treat obesity and T2D. However, there are some outstanding issues regarding the use of mirabegron to activate BAT. First, there has been no direct comparison of the effect of acute cold vs. mirabegron on BAT metabolism. Second, there has been no demonstration of the effect of mirabegron on BAT oxidative metabolism since glucose uptake is only a surrogate of BAT energy expenditure. Third, acute administration of mirabegron led to significant increases in blood pressure and cardiac work, suggesting that it may also enhance energy expenditure in other organs in addition to BAT, thus confounding the role of BAT in energy homeostasis. Therefore, much remains to be known about the effect of mirabegron on BAT and cardiac energy metabolism before this drug can be used as a selective activator of BAT oxidative metabolism. The purpose of this study is to directly compare BAT oxidative metabolism under cold vs. β3-adrenergic agonist stimulation in lean healthy individuals. The investigator hypothesizes that the acute oral administration of a lower dose of mirabegron (50 mg) will result in an increase in BAT oxidative metabolism and whole-body energy expenditure, to a similar extent as cold exposure, without influencing the cardiovascular responses previously seen with the higher dose (200 mg).

• Phase: N/A
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Université de Sherbrooke
• Treatments: Glycerol; Mirabegron

Criteria

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.