Chronic ephedrine administration decreases brown adipose tissue activity in a randomised controlled human trial: implications for obesity

Carey, Andrew L.; Pajtak, Renata; Formosa, Melissa F.; Every, Bruce Van; Bertovic, David A.; Anderson, Mitchell; Eikelis, Nina; Lambert, Gavin W.; Kalff, Victor; Duffy, Stephen J.; Cherk, Martin H; Kingwell, Bronwyn A.

doi:10.1007/s00125-015-3543-6

Cited by 42 publications

(55 citation statements)

References 48 publications

(87 reference statements)

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“…Experimental protocol for BAT activation trial Initial screening involved clinical history and examination by a physician [7].…”

Section: Methodsmentioning

confidence: 99%

“…PET/CT imaging PET/CT imaging and analyses were conducted as previously described [7,24], except PET/CT image acquisition and reconstruction was carried out using a GE Discovery 710 PET/CT scanner (GE, Fairfield, CT, USA) and analysis was performed using MIM software v6.6 (MIM Software, Cleveland, OH, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Biochemical analyses Where indicated, plasma was centrifuged and frozen for analyses or whole blood was collected in an appropriate preservative and measured immediately as described [7,24].…”

Section: Methodsmentioning

confidence: 99%

“…In mice, chronic administration of the sympathomimetic ephedrine increased uncoupling protein-1 (UCP-1) content and BAT activity [6]. However, when the pan-β-adrenergic receptor agonist, ephedrine, was administered for 4 weeks to humans, BAT glucose uptake decreased [7]. This effect, likely due to downregulation of β 1/2 -adrenergic receptor signalling, highlighted distinct species differences between humans and rodents and the necessity to identify alternate approaches.…”

Section: Introductionmentioning

confidence: 99%

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Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans

et al. 2017

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Aims/hypothesis Increasing brown adipose tissue (BAT) activity is a possible therapeutic strategy to increase energy expenditure and glucose and lipid clearance to ameliorate obesity and associated comorbidities. The thiazolidinedione (TZD) class of glucose-lowering drugs increase BAT browning in preclinical experimental models but whether these actions extend to humans in vivo is unknown. The aim of this study was to determine the effect of pioglitazone treatment on adipocyte browning and adaptive thermogenesis in humans. Methods We first examined whether pioglitazone treatment of cultured human primary subacromioclavicular-derived adipocytes induced browning. Then, in a blinded, placebo-controlled, parallel trial, conducted within the Baker Institute clinical research laboratories, 14 lean male participants who were free of cardiometabolic disease were randomised to receive either placebo (lactose; n = 7, age 22 ± 1 years) or pioglitazone (45 mg/day, n = 7, age 21 ± 1 years) for 28 days. Participants were allocated to treatments by Alfred Hospital staff independent from the study via electronic generation of a random number sequence. Researchers conducting trials and analysing data were blind to treatment allocation. The change in cold-stimulated BAT activity, assessed before and after the intervention by [ 18 F]fluorodeoxyglucose uptake via positron emission tomography/computed tomography in upper thoracic and cervical adipose tissue, was the primary outcome measure. Energy expenditure, cardiovascular responses, core temperature, blood metabolites and hormones were measured in response to acute cold exposure along with body composition before and after the intervention. Results Pioglitazone significantly increased in vitro browning and adipogenesis of adipocytes. In the clinical trial, coldElectronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-017-4479-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. -017-4479-9 induced BAT maximum standardised uptake value was significantly reduced after pioglitazone compared with placebo (−57 ± 6% vs −12 ± 18%, respectively; p < 0.05). BAT total glucose uptake followed a similar but non-significant trend (−50 ± 10% vs −6 ± 24%, respectively; p = 0.097). Pioglitazone increased total and lean body mass compared with placebo (p < 0.05). No other changes between groups were detected. Conclusions/interpretation The disparity in the actions of pioglitazone on BAT between preclinical experimental models and our in vivo human trial highlight the imperative to conduct human proof-of-concept studies as early as possible in BAT research programmes aimed at therapeutic development. Our clinical trial findings suggest that reduced BAT activity may contribute to weight gain associated with pioglitazone and other TZDs.Trial registration ClinicalTrials.gov NCT02236962

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“…Experimental protocol for BAT activation trial Initial screening involved clinical history and examination by a physician [7].…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans

et al. 2017

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“…Likewise, it has been shown that chronic ephedrine treatment in healthy young men led to a decrease in brown adipose tissue activity in parallel with a reduction in body fat content (12). One explanation for the findings in Nakhuda et al could be that local mechanisms in white adipose tissue (e.g., via blood-flow regulation) restrict the release of fatty acids so that toxic concentrations are not reached.…”

mentioning

confidence: 76%

Is human white adipose tissue bright during exercise?

Bülow

2016

The American Journal of Clinical Nutrition

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Sheep as a Model for Control of Appetite and Energy Expenditure

Henry

Clarke

2018

Model Animals in Neuroendocrinology

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Chronic ephedrine administration decreases brown adipose tissue activity in a randomised controlled human trial: implications for obesity

Abstract: 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.

Cited by 42 publications

References 48 publications

Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans

Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans

Is human white adipose tissue bright during exercise?

Sheep as a Model for Control of Appetite and Energy Expenditure

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