title: Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice.
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[(3)H]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.
authors.affiliation: Department of General Internal Medicine, Endocrinology, and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Janine J
authors.initials: JJ
authors.lastname: Geerling
authors.forename: Mariëtte R
authors.initials: MR
authors.lastname: Boon
authors.forename: Gerard C
authors.initials: GC
authors.lastname: van der Zon
authors.forename: Sjoerd A A
authors.initials: SA
authors.lastname: van den Berg
authors.forename: Anita M
authors.initials: AM
authors.lastname: van den Hoek
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.forename: Hans M G
authors.initials: HM
authors.lastname: Princen
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.forename: Bruno
authors.initials: B
authors.lastname: Guigas
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D050171:Dyslipidemias / Q000188:drug therapy; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008066:Lipolysis / Q000187:drug effects; D008071:Lipoprotein Lipase / Q000502:physiology; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D014280:Triglycerides / Q000097:blood* / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D008687:Metformin; D002784:Cholesterol; D055372:AMP-Activated Protein Kinases; D008071:Lipoprotein Lipase