title: Melatonin attenuated adipogenesis through reduction of the CCAAT/enhancer binding protein beta by regulating the glycogen synthase 3 beta in human mesenchymal stem cells.
abstract: Adipogenic differentiation is characterized by an increase in two major transcription factors: peroxisome proliferator-activated receptor gamma (PPARγ) and the CCAAT/enhancer binding protein alpha (C/EBPα). These two signals are influenced by C/EBPβ and C/EBPδ and cross-regulate each other's expression during the initial stages of adipogenesis. Melatonin has been known to act as not only a direct scavenger of free radicals but also an inhibitor of glycogen synthase kinase 3β (GSK-3β). Here, we report that melatonin inhibits the adipogenic differentiation of human mesenchymal stem cells (hMSCs) which is due to the regulations of C/EBPβ in the early stage of adipogenic differentiation. Melatonin reduced the lipid accumulation, adiponectin, and lipoprotein lipase (LPL) during the adipogenic differentiation of hMSCs. Since C/EBPβ has been associated with the activation of PPARγ and the consensus site of ERK/GSK-3β, PPARγ and β-catenin were detected by immunofluorescence staining after pretreatment of melatonin. Melatonin blocked the activation of PPARγ which induced the degradation of β-catenin. Melatonin also decreased the levels of cyclic adenosine-3,5-monophosphate (cAMP) and reactive oxygen species (ROS). The cAMP triggered the activity of C/EBPβ which is a critical inducer of PPARγ and C/EBPα activation in the early stage of adipogenic differentiation, and this is further affected by ROS production. The adipogenic marker proteins such as PPARγ, C/EBPα, C/EBPβ, and pERK were also decreased by melatonin. In summary, melatonin inhibited the cAMP synthesis through ROS reduction and the phosphorylation of the ERK/GSK-3β site which is known to be responsible for C/EBPβ activation for adipogenic differentiation in hMSCs.
authors.affiliation: Beckman Laser Institute Korea, Dankook University, Cheonan, Chungnam, 31116, Republic of Korea.
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Rhee
authors.affiliation: Beckman Laser Institute Korea, Dankook University, Cheonan, Chungnam, 31116, Republic of Korea. jcahn@dankook.ac.kr.|Department of Biomedical Science, College of Medicine, Dankook University, Cheonan, Chungnam, 31116, Republic of Korea. jcahn@dankook.ac.kr.|Institute of Biomedical Translational Research, Dankook University, Cheonan, Chungnam, 31116, Republic of Korea. jcahn@dankook.ac.kr.
authors.forename: Jin-Chul
authors.initials: JC
authors.lastname: Ahn
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D050156:Adipogenesis; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D050356:Lipid Metabolism; D008550:Melatonin / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015290:Second Messenger Systems
chemical_list: D015415:Biomarkers; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D008024:Ligands; D017382:Reactive Oxygen Species; D000242:Cyclic AMP; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D008550:Melatonin
keywords: Adipogenesis; C/EBPβ; GSK3β/ERK; Melatonin; ROS; hMSC