Regulation of Wnt signaling during adipogenesis.
We have identified Wnt10b as a potent inhibitor of adipogenesis that must be suppressed for preadipocytes to differentiate in vitro. Here, we demonstrate that a specific inhibitor of glycogen synthase kinase 3, CHIR 99021, mimics Wnt signaling in preadipocytes. CHIR 99021 stabilizes free cytosolic beta-catenin and inhibits adipogenesis by blocking induction of CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. Preadipocyte differentiation is inhibited when 3T3-L1 cells are exposed to CHIR 99021 for any 24 h period during the first 3 days of adipogenesis. Consistent with this time frame of inhibition, expression of Wnt10b mRNA is suppressed upon induction of differentiation, with a 50% decline by 6 h and complete inhibition by 36 h. Of the agents used to induce differentiation, exposure of 3T3-L1 cells to methyl-isobutylxanthine or cAMP is sufficient to suppress expression of Wnt10b mRNA. Inhibition of adipogenesis by Wnt10b is likely mediated by Wnt receptors, Frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 6. These receptors, like Wnt10b, are highly expressed in preadipocytes and stromal vascular cells. Finally, we demonstrate that disruption of extracellular Wnt signaling by expression of secreted Frizzled related proteins causes spontaneous adipocyte conversion.
Bennett
Christina N
CN
Department of Physiology, 7620 Medical Science II, University of Michigan Medical School, 1301 E. Catherine Street, Ann Arbor, MI 48109-0622, USA.
Ross
Sarah E
SE
Longo
Kenneth A
KA
Bajnok
Laszlo
L
Hemati
Nahid
N
Johnson
Kirk W
KW
Harrison
Stephen D
SD
MacDougald
Ormond A
OA
D016475:3T3 Cells; D017667:Adipocytes / Q000502:physiology*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000037:antagonists & inhibitors; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002454:Cell Differentiation; D000242:Cyclic AMP / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D013234:Stem Cells / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D051153:Wnt Proteins
D022763:CCAAT-Enhancer-Binding Protein-alpha; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse; D000242:Cyclic AMP; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3