Wnt signaling protects 3T3-L1 preadipocytes from apoptosis through induction of insulin-like growth factors.
Ectopic expression of Wnt-1 in 3T3-L1 preadipocytes stabilizes beta-catenin, activates TCF-dependent gene transcription, and blocks adipogenesis. Here we report that upon serum withdrawal, Wnt-1 causes 3T3-L1 cells to resist apoptosis through a mechanism that is partially dependent on phosphatidylinositol 3-kinase. Although activation of Wnt signaling by inhibition of GSK-3 activity or ectopic expression of dominant stable beta-catenin blocks apoptosis, inhibition of Wnt signaling through expression of dominant negative TCF-4 increases apoptosis. Wnt-1 stimulates 3T3-L1 preadipocytes to secrete factors that increase PKB/Akt phosphorylation at levels comparable with treatment with 10% serum. With DNA microarrays, we identified several secreted antiapoptotic genes that are induced by Wnt-1, notably insulin-like growth factor I (IGF-I) and IGF-II. Consistent with IGFs mediating the antiapoptotic effects of Wnt-1 in preadipocytes, conditioned medium from Wnt-1 expressing 3T3-L1 cells was unable to promote protein kinase B phosphorylation after the addition of recombinant IGFBP-4. Thus, we demonstrated that Wnt-1 induces expression of antiapoptotic genes in 3T3-L1 preadipocytes such as IGF-I and IGF-II, which allows these cells to resist apoptosis in response to serum deprivation.
Longo
Kenneth A
KA
Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622, USA.
Kennell
Jennifer A
JA
Ochocinska
Margaret J
MJ
Ross
Sarah E
SE
Wright
Wendy S
WS
MacDougald
Ormond A
OA
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D008094:Lithium / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins; D051155:Wnt1 Protein; D000077191:Wortmannin; D029961:Zebrafish Proteins; D051176:beta Catenin
D000730:Androstadienes; D002867:Chromones; D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D008094:Lithium; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D015534:Trans-Activators; D051153:Wnt Proteins; D051155:Wnt1 Protein; D000077191:Wortmannin; D029961:Zebrafish Proteins; D051176:beta Catenin; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C495247:WNT1 protein, human; C495246:Wnt1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human