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- Title
Metformin Lowers Plasma Triglycerides by Promoting VLDL-Triglyceride Clearance by Brown Adipose Tissue in Mice.
- Authors
Geerling, Janine J.; Boon, Mariëtte R.; van der Zon, Gerard C.; den Berg, Sjoerd A. A. van; den Hoek, Anita M. van; Lombès, Marc; Princen, Hans M. G.; Havekes, Louis M.; Rensen, Patrick C. N.; Guigas, Bruno
- Abstract
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.
- Subjects
TYPE 2 diabetes treatment; BROWN adipose tissue; TRIGLYCERIDES; LIPOPROTEINS; LABORATORY mice
- Publication
Diabetes, 2014, Vol 63, Issue 3, p880
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db13-0194