Metadoxine, an ion-pair of pyridoxine and L-2-pyrrolidone-5-carboxylate, blocks adipocyte differentiation in association with inhibition of the PKA-CREB pathway.
Adipogenesis is orchestrated by the expression of master adipogenic regulators. In particular, phosphorylation of cAMP response element binding protein (CREB) by protein kinase A promotes CREB nuclear translocation, thereby inducing expression of the adipogenic regulators and resulting in adipogenic maturation. Although metadoxine, an ion-pair of pyridoxine and l-2-pyrrolidone-5-carboxylate, has been shown to inhibit lipid accumulation in the liver, its effect on adipocyte differentiation has never been explored. This study investigated the effects of metadoxine on the differentiation of 3T3-L1 preadipocytes and the molecular mechanism. Metadoxine treatment did not inhibit mitotic clonal expansion, but inhibited late-stage cell differentiation, suggesting that metadoxine may block the differentiation step of preadipocytes. Metadoxine inhibited CREB phosphorylation and binding to the cAMP response element, thereby repressing CCAAT/enhancer-binding protein beta during hormone-induced adipogenesis. Overall, metadoxine inhibits adipogenic differentiation in association with the inhibition of CREB/cAMP response element-dependent CCAAT/enhancer-binding protein beta induction in the protein kinase A-CREB pathway.
Yang
Yoon Mee
YM
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, South Korea.
Kim
Hyun Eun
HE
Ki
Sung Hwan
SH
Kim
Sang Geon
SG
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism* / Q000502:physiology; D050156:Adipogenesis / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004789:Enzyme Activation / Q000187:drug effects; D017930:Genes, Reporter; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011736:Pyridoxine / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000737:chemistry; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
D017362:Cyclic AMP Response Element-Binding Protein; D004338:Drug Combinations; D011760:Pyrrolidinones; D008156:Luciferases; D017868:Cyclic AMP-Dependent Protein Kinases; C037845:metadoxine; C028537:2-pyrrolidone; D011736:Pyridoxine; D011761:Pyrrolidonecarboxylic Acid