Diabetologia

pp 1–11 | Cite as

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

  • Rebecca K. C. Loh
  • Melissa F. Formosa
  • Nina Eikelis
  • David A. Bertovic
  • Mitchell J. Anderson
  • Shane A. Barwood
  • Shane Nanayakkara
  • Neale D. Cohen
  • Andre La Gerche
  • Anne T. Reutens
  • Kenneth S. Yap
  • Thomas W. Barber
  • Gavin W. Lambert
  • Martin H. Cherk
  • Stephen J. Duffy
  • Bronwyn A. Kingwell
  • Andrew L. Carey
Article

Abstract

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 [18F]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, cold-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

Funding

This work was supported by the Diabetes Australia Research Program and OIS scheme from the Victorian State Government.

Keywords

Adaptive thermogenesis BAT Energy expenditure Noradrenaline Norepinephrine Obesity Thiazolidinedione Type 2 diabetes TZD UCP-1 Uncoupling protein-1 

Abbreviations

BAT

Brown adipose tissue

BAT TGU

BAT total glucose uptake

[18F]FDG

[18F]Fluorodeoxyglucose

PET/CT

Positron emission tomography/computed tomography

PPARγ

Peroxisome proliferator-activated receptor γ

RER

Respiratory exchange ratio

SUV

Standardised uptake value

TSH

Thyroid-stimulating hormone

TZD

Thiazolidinedione

UCP-1

Uncoupling protein-1

Supplementary material

125_2017_4479_MOESM1_ESM.pdf (184 kb)
ESM Tables(PDF 183 kb)

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Rebecca K. C. Loh
    • 1
  • Melissa F. Formosa
    • 1
  • Nina Eikelis
    • 2
    • 3
  • David A. Bertovic
    • 1
  • Mitchell J. Anderson
    • 1
    • 4
  • Shane A. Barwood
    • 4
  • Shane Nanayakkara
    • 5
  • Neale D. Cohen
    • 6
  • Andre La Gerche
    • 7
  • Anne T. Reutens
    • 6
  • Kenneth S. Yap
    • 8
    • 9
  • Thomas W. Barber
    • 8
    • 9
  • Gavin W. Lambert
    • 2
    • 3
  • Martin H. Cherk
    • 8
    • 9
  • Stephen J. Duffy
    • 5
  • Bronwyn A. Kingwell
    • 1
  • Andrew L. Carey
    • 1
  1. 1.Metabolic and Vascular Physiology LaboratoryBaker Heart and Diabetes InstituteMelbourneAustralia
  2. 2.Human Neurotransmitters LaboratoryBaker Heart and Diabetes InstituteMelbourneAustralia
  3. 3.Iverson Health Innovation Research Institute, Swinburne Institute of TechnologyMelbourneAustralia
  4. 4.Melbourne Orthopaedic GroupWindsorAustralia
  5. 5.Department of Cardiovascular MedicineAlfred HospitalMelbourneAustralia
  6. 6.Baker Heart and Diabetes InstituteMelbourneAustralia
  7. 7.Sports Cardiology LaboratoryBaker Heart and Diabetes InstituteMelbourneAustralia
  8. 8.The Department of Nuclear Medicine and PET, Alfred HealthMelbourneAustralia
  9. 9.Department of MedicineMonash UniversityMelbourneAustralia

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