Metformin Lowers Plasma Triglycerides by Promoting VLDL-Triglyceride Clearance by Brown Adipose Tissue in Mice
- Janine J. Geerling1,2,
- Mariëtte R. Boon1,2,
- Gerard C. van der Zon3,
- Sjoerd A.A. van den Berg4,
- Anita M. van den Hoek5,
- Marc Lombès6,
- Hans M.G. Princen5,
- Louis M. Havekes1,2,5,
- Patrick C.N. Rensen1,2 and
- Bruno Guigas2,3⇑
- 1Department of General Internal Medicine, Endocrinology, and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands
- 2Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
- 3Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
- 4Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
- 5Gaubius Laboratory, Netherlands Organization for Applied Scientific Research-Metabolic Health Research, Leiden, the Netherlands
- 6INSERM, U693, Faculté de Médecine Paris-Sud, Université Paris-Sud, Le Kremlin-Bicêtre, France
- 7Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands
- Corresponding author: Bruno Guigas, .
J.J.G., M.R.B., P.C.N.R., and B.G. contributed equally to this study.
Metformin is the first-line drug for the treatment of type 2 diabetes. Besides its well-characterized antihyperglycemic properties, metformin also lowers plasma VLDL triglyceride (TG). In this study, we investigated the underlying mechanisms in APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism. We found that metformin markedly lowered plasma total cholesterol and TG levels, an effect mostly due to a decrease in VLDL-TG, whereas HDL was slightly increased. Strikingly, metformin did not affect hepatic VLDL-TG production, VLDL particle composition, and hepatic lipid composition but selectively enhanced clearance of glycerol tri[3H]oleate-labeled VLDL-like emulsion particles into brown adipose tissue (BAT). BAT mass and lipid droplet content were reduced in metformin-treated mice, pointing to increased BAT activation. In addition, both AMP-activated protein kinase α1 (AMPKα1) expression and activity and HSL and mitochondrial content were increased in BAT. Furthermore, therapeutic concentrations of metformin increased AMPK and HSL activities and promoted lipolysis in T37i differentiated brown adipocytes. Collectively, our results identify BAT as an important player in the TG-lowering effect of metformin by enhancing VLDL-TG uptake, intracellular TG lipolysis, and subsequent mitochondrial fatty acid oxidation. Targeting BAT might therefore be considered as a future therapeutic strategy for the treatment of dyslipidemia.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0194/-/DC1.
S.A.A.v.d.B. is currently affiliated with the Laboratory for Clinical Chemistry and Hematology, Amphia Hospital, Breda, the Netherlands.
- Received February 4, 2013.
- Accepted November 17, 2013.
- © 2014 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.