Brown Adipose Tissue is a Putative Metformin Target

Abstract

Metformin is the most widely prescribed oral antidiabetic drug worldwide. In spite of well-documented beneficial effects on diabetes, target organs that mediate its effects remain to be established. In recent years, active brown adipose tissue (BAT) has been found in the deep neck of adult humans. Under the hypothesis that brown adipose tissue (BAT) is a metformin target tissue we investigated metformin uptake in vivo and studied the in vitro effects of metformin on cultured human brown adipocytes. Tissue-specific uptake of metformin was assessed by PET/CT imaging after injection of [(11)C]-metformin in mice. Human brown adipose tissue was obtained from elective neck surgery and OCT expression levels in human and murine BAT were determined by qPCR. Oxygen consumption in immortalized brown adipocytes of human origin (TERT-hBA) during metformin exposure was assessed by Seahorse XF technology. Injection of C11-metformin in mice revealed avid uptake in the interscapular BAT depot. Metformin exposure in BAT was comparable to hepatic exposure. Inhibition of OCT1, OCT2 and MATE1 function did not affect BAT exposure to metformin suggesting OCT3 mediated uptake. Determination of OCT3 mRNA expression in BAT supported this assumption. OCT3 levels were >5000 fold higher than other metformin transporter genes in mouse BAT and 50-500 times higher in the adipose tissue from human deep neck. In vitro incubation of TERT-hBA cells with metformin inhibited cellular oxygen consumption. This effect was dose dependent with oxygen consumption seemingly settling at a lower rate. Metformin is transported into BAT in mice. This transport is likely mediated through OCT3. OCT3 is present in human brown adipocytes making an effect in human BAT likely. Metformin inhibits mitochondrial respiration in cultured brown adipocytes. Collectively, this suggests BAT as a putative metformin target in humans.