Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice
- Janine J. Geerling1,
- Mariëtte R. Boon1,
- Gerard C. van der Zon2,
- Sjoerd A.A. van den Berg3,†,
- Anita M. van den Hoek4,
- Marc Lombès5,
- Hans M.G. Princen4,
- Louis M. Havekes1,4,
- Patrick C.N Rensen1 and
- Bruno Guigas2,6⇑
- 1Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
- 2Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
- 3Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
- 4Gaubius Laboratory, Netherlands Organization for Applied Scientific Research-Metabolic Health Research, Leiden, The Netherlands.
- 5INSERM, U693, Facultéde Médecine Paris-Sud, Université Paris-Sud, UMR-S693, Le Kremlin-Bicêtre, France.
- 6Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.
- Address for correspondence:
Dr. Bruno Guigas, E-Mail:
Metformin is the first-line drug for the treatment of type 2 diabetes. Besides its well-characterized anti-hyperglycemic properties, metformin also lowers plasma very low-density lipoprotein (VLDL)-triglycerides (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 a decrease in VLDL-TG whereas high-density lipoprotein 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 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.
Janine J. Geerling and Mariëtte R. Boon contributed equally to this study.
Patrick C.N. Rensen and Bruno Guigas contributed equally to this study.
† Present address: Amphia Hospital, Laboratory for Clinical Chemistry & Hematology, Breda, The Netherlands.
- Received February 4, 2013.
- Accepted November 17, 2013.
- © 2013 by the American Diabetes Association.
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