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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Resumé

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.

OriginalsprogEngelsk
TidsskriftDiabetes, Obesity and Metabolism
Vol/bind20
Udgave nummer9
Sider (fra-til)2264-2273
ISSN1462-8902
DOI
StatusUdgivet - sep. 2018

Fingeraftryk

Oxygen Consumption
Brown Adipocytes
In Vitro Techniques
Cations
Smegmamorpha
Cimetidine
Transcriptome

Citer dette

Breining, P., Jensen, J. B., Sundelin, E. I., Gormsen, L. C., Jakobsen, S., Busk, M., ... Jessen, N. (2018). Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro. Diabetes, Obesity and Metabolism, 20(9), 2264-2273. https://doi.org/10.1111/dom.13362
Breining, Peter ; Jensen, Jonas B ; Sundelin, Elias I ; Gormsen, Lars C ; Jakobsen, Steen ; Busk, Morten ; Rolighed, Lars ; Bross, Peter ; Fernandez-Guerra, Paula ; Markussen, Lasse K ; Rasmussen, Nanna E ; Hansen, Jacob B. ; Pedersen, Steen B ; Richelsen, Bjørn ; Jessen, Niels. / Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro. I: Diabetes, Obesity and Metabolism. 2018 ; Bind 20, Nr. 9. s. 2264-2273.
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title = "Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro",
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.",
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author = "Peter Breining and Jensen, {Jonas B} and Sundelin, {Elias I} and Gormsen, {Lars C} and Steen Jakobsen and Morten Busk and Lars Rolighed and Peter Bross and Paula Fernandez-Guerra and Markussen, {Lasse K} and Rasmussen, {Nanna E} and Hansen, {Jacob B.} and Pedersen, {Steen B} and Bj{\o}rn Richelsen and Niels Jessen",
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Breining, P, Jensen, JB, Sundelin, EI, Gormsen, LC, Jakobsen, S, Busk, M, Rolighed, L, Bross, P, Fernandez-Guerra, P, Markussen, LK, Rasmussen, NE, Hansen, JB, Pedersen, SB, Richelsen, B & Jessen, N 2018, 'Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro', Diabetes, Obesity and Metabolism, bind 20, nr. 9, s. 2264-2273. https://doi.org/10.1111/dom.13362

Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro. / Breining, Peter; Jensen, Jonas B; Sundelin, Elias I; Gormsen, Lars C; Jakobsen, Steen; Busk, Morten; Rolighed, Lars; Bross, Peter; Fernandez-Guerra, Paula; Markussen, Lasse K; Rasmussen, Nanna E; Hansen, Jacob B.; Pedersen, Steen B; Richelsen, Bjørn; Jessen, Niels.

I: Diabetes, Obesity and Metabolism, Bind 20, Nr. 9, 09.2018, s. 2264-2273.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro

AU - Breining, Peter

AU - Jensen, Jonas B

AU - Sundelin, Elias I

AU - Gormsen, Lars C

AU - Jakobsen, Steen

AU - Busk, Morten

AU - Rolighed, Lars

AU - Bross, Peter

AU - Fernandez-Guerra, Paula

AU - Markussen, Lasse K

AU - Rasmussen, Nanna E

AU - Hansen, Jacob B.

AU - Pedersen, Steen B

AU - Richelsen, Bjørn

AU - Jessen, Niels

N1 - © 2018 John Wiley & Sons Ltd.

PY - 2018/9

Y1 - 2018/9

N2 - 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.

AB - 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.

KW - antidiabetic drug

KW - drug mechanism

KW - metformin

KW - pharmacokinetics

KW - type 2 diabetes

U2 - 10.1111/dom.13362

DO - 10.1111/dom.13362

M3 - Journal article

VL - 20

SP - 2264

EP - 2273

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 9

ER -

Breining P, Jensen JB, Sundelin EI, Gormsen LC, Jakobsen S, Busk M et al. Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro. Diabetes, Obesity and Metabolism. 2018 sep;20(9):2264-2273. https://doi.org/10.1111/dom.13362