Pharmacological Activation of Brown Adipose Tissue Metabolism
Status:
Completed
Trial end date:
2018-07-05
Target enrollment:
Participant gender:
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).