Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro

Peter Breining, Jonas B Jensen, Elias I Sundelin, Lars C Gormsen, Steen Jakobsen, Morten Busk, Lars Rolighed, Peter Bross, Paula Fernandez-Guerra, Lasse K Markussen, Nanna E Rasmussen, Jacob B. Hansen, Steen B Pedersen, Bjørn Richelsen, Niels Jessen

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Abstract

AIMS: To test the hypothesis that brown adipose tissue (BAT) is a metformin target tissue by investigating in vivo uptake of [11 C]-metformin tracer in mice and studying in vitro effects of metformin on cultured human brown adipocytes.

MATERIALS AND METHODS: Tissue-specific uptake of metformin was assessed in mice by PET/CT imaging after injection of [11 C]-metformin. Human brown adipose tissue was obtained from elective neck surgery and metformin transporter expression levels in human and murine BAT were determined by qPCR. Oxygen consumption in metformin-treated human brown adipocyte cell models was assessed by Seahorse XF technology.

RESULTS: Injected [11 C]-metformin showed avid uptake in the murine interscapular BAT depot. Metformin exposure in BAT was similar to hepatic exposure. Non-specific inhibition of the organic cation transporter (OCT) protein by cimetidine administration eliminated BAT exposure to metformin, demonstrating OCT-mediated uptake. Gene expression profiles of OCTs in BAT revealed ample OCT3 expression in both human and mouse BAT. Incubation of a human brown adipocyte cell models with metformin reduced cellular oxygen consumption in a dose-dependent manner.

CONCLUSION: These results support BAT as a putative metformin target.

Original languageEnglish
JournalDiabetes, Obesity and Metabolism
Volume20
Issue number9
Pages (from-to)2264-2273
ISSN1462-8902
DOIs
Publication statusPublished - Sep 2018

Keywords

  • antidiabetic drug
  • drug mechanism
  • metformin
  • pharmacokinetics
  • type 2 diabetes

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