Chronic ephedrine administration decreases brown adipose tissue activity in a randomised controlled human trial: implications for obesity.
OBJECTIVE
Brown adipose tissue (BAT) activation increases energy expenditure and may have therapeutic potential to combat obesity. The primary activating and adaptive signal for BAT is via β-adrenergic signalling. We previously demonstrated that human BAT is acutely responsive to oral administration of the sympathomimetic, ephedrine. Here we aimed to determine whether adaptive thermogenesis can be induced via chronic treatment with ephedrine.


METHODS
Twenty-three healthy young men, recruited from the general public in Melbourne, Australia, who were non-smokers, physically inactive and non-medicated with no prior history of cardiovascular disease or diabetes were recruited for this study. They were assigned to receive either 1.5 mg kg(-1) day(-1) ephedrine ('active' group; n = 12, age 23 ± 1 years, BMI 24 ± 1 kg/m(2)) or placebo (n = 11; 22 ± 2 years, 23 ± 2 kg/m(2)) for 28 days in a randomised (computer-generated random order sequence), placebo-controlled, parallel-group trial. Participants and all investigators were blinded to treatments. Body composition was measured before and after the intervention by dual energy X-ray absorptiometry. BAT activity, measured via (18)F-fluorodeoxyglucose positron emission tomography-computed tomography, in response to a single dose of 2.5 mg/kg ephedrine, was the primary outcome measure to be determined before and after the 28 day treatment period.


RESULTS
Twenty-eight individuals were randomised and consented to the study. Twenty-three completed the trial and only these participants were included in the final analyses. After 28 days of treatment, the active group lost a significant amount of total body fat (placebo 1.1 ± 0.3 kg, ephedrine -0.9 ± 0.5 kg; p < 0.01) and visceral fat (placebo 6.4 ± 19.1 g, ephedrine -134 ± 43 g; p < 0.01), with no change in lean mass or bone mineral content compared with the placebo group. In response to acute ephedrine, BAT activity (change in mean standardised uptake value: placebo -3 ± 7%, ephedrine -22 ± 6%) and the increase in systolic blood pressure were significantly reduced (p < 0.05) in the active group compared with placebo.


CONCLUSIONS
Chronic ephedrine treatment reduced body fat content, but this was not associated with an increase in BAT activity. Rather, chronic ephedrine suppressed BAT glucose disposal, suggesting that chronic ephedrine treatment decreased, rather than increased, BAT activity.


BACKGROUND
ClinicalTrials.gov NCT02236962 FUNDING: This study was funded by the National Health and Medical Research Council of Australia Program Grant (1036352) and the OIS scheme from the Victorian State Government.
Metabolic and Vascular Physiology Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia, andrew.carey@bakeridi.edu.au.
Andrew L
AL
Carey
Renata
R
Pajtak
Melissa F
MF
Formosa
Bruce
B
Van Every
David A
DA
Bertovic
Mitchell J
MJ
Anderson
Nina
N
Eikelis
Gavin W
GW
Lambert
Victor
V
Kalff
Stephen J
SJ
Duffy
Martin H
MH
Cherk
Bronwyn A
BA
Kingwell
D002001:Adipose Tissue, Brown / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D001786:Blood Glucose; D001794:Blood Pressure / Q000502:physiology; D001823:Body Composition / Q000187:drug effects*; D004809:Ephedrine / Q000494:pharmacology* / Q000627:therapeutic use; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008297:Male; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D011877:Radionuclide Imaging; D013566:Sympathomimetics / Q000494:pharmacology* / Q000627:therapeutic use; D022722:Thermogenesis / Q000187:drug effects*; D055815:Young Adult
D001786:Blood Glucose; D013566:Sympathomimetics; D019788:Fluorodeoxyglucose F18; D004809:Ephedrine