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

Diabetes, Obesity and Metabolism - Tập 20 Số 9 - Trang 2264-2273 - 2018
Peter Breining1,2, Jonas Jensen3, Elias Sundelin3, Lars Christian Gormsen4, Steen Jakobsen4, Morten Busk5, Lars Rolighed6, Peter Bross7, Paula Fernández‐Guerra7, Lasse K. Markussen8,9, Nanna E. Rasmussen9, Jacob B. Hansen9, Steen B. Pedersen2, Bjørn Richelsen2, Niels Jessen10,3,1
1Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark
2Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
3Department of Clinical Medicine, Research Laboratory for Biochemical Pathology, Aarhus University, Aarhus, Denmark
4Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
5Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
6Department of Otorhinolaryngology and Department of Surgery P, Aarhus University Hospital, Aarhus, Denmark
7Department of Clinical Medicine, Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark
8Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
9Department of Biology, University of Copenhagen, Copenhagen, Denmark
10Department of Biomedicine, Aarhus University, Aarhus, Denmark

Tóm tắt

AimsTo test the hypothesis that brown adipose tissue (BAT) is a metformin target tissue by investigating in vivo uptake of [11C]‐metformin tracer in mice and studying in vitro effects of metformin on cultured human brown adipocytes.Materials and methodsTissue‐specific uptake of metformin was assessed in mice by PET/CT imaging after injection of [11C]‐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.ResultsInjected [11C]‐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.ConclusionThese results support BAT as a putative metformin target.

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Diabetes, Obesity and Metabolism

Tập 20 Số 9

2264-2273

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