Pharmacological Activation of Brown Adipose Tissue Metabolism

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).

Conditions

• Type 2 Diabetes

Interventions

DRUG

Mirbetriq (Mirabegron)

50mg of Mirabegron will be administered orally at time 0 in protocol A.

OTHER

cold exposure

Acute cold exposure protocol using a water-conditioned cooling suit will be applied from time 120 to 300 min in protocol B

RADIATION

injection of 18FDG

I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed at time 270 min, followed by 30 min dynamic PET/CT scanning

RADIATION

injection of 11C-acetate

i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning

RADIATION

[3-3H]-glucose

i.v. administration of 1.5 uCi/min of \[3-3H\]-glucose

OTHER

[U-13C]-palmitate

i.v. administration of 0.08 umol/kg/min of \[U-13C\]-palmitate

OTHER

2H-Glycerol

i.v. administration of 0.05 µmol/kg/min of 2H-glycerol

Sponsors & Collaborators

• Université de Sherbrooke

  lead OTHER

Principal Investigators

• André Carpentier, M.D. · Centre de recherche du CHUS

Study Design

Allocation

RANDOMIZED

Purpose

OTHER

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

45 Years

Sex

MALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2016-08-05

Primary Completion

2018-05-24

Completion

2018-07-05

Countries

• Canada

Study Locations