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

Aims: To test the hypothesis that brown adipose tissue (BAT) is a metformin target tissue by investigating in vivo uptake of [C-11]-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 [C-11]-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 [C-11]-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.