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PI3K/Akt is involved in brown adipogenesis mediated by growth differentiation factor-5 in association with activation of the Smad pathway
Authors:Eiichi Hinoi  Takashi IezakiHiroyuki Fujita  Takumi WatanabeYoshiaki Odaka  Kakeru OzakiYukio Yoneda
Affiliation:Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa 920-1192, Japan
Abstract:
We have previously demonstrated promotion by growth differentiation factor-5 (GDF5) of brown adipogenesis for systemic energy expenditure through a mechanism relevant to activating the bone morphological protein (BMP) receptor/mothers against decapentaplegic homolog (Smad)/peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) pathway. Here, we show the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in brown adipogenesis mediated by GDF5. Overexpression of GDF5 in cells expressing adipocyte protein-2 markedly accelerated the phosphorylation of Smad1/5/8 and Akt in white and brown adipose tissues. In brown adipose tissue from heterozygous GDF5Rgsc451 mutant mice expressing a dominant-negative (DN) GDF5 under obesogenic conditions, the basal phosphorylation of Smad1/5/8 and Akt was significantly attenuated. Exposure to GDF5 not only promoted the phosphorylation of both Smad1/5/8 and Akt in cultured brown pre-adipocytes, but also up-regulated Pgc1a and uncoupling protein-1 expression in a manner sensitive to the PI3K/Akt inhibitor Ly294002 as well as retroviral infection with DN-Akt. GDF5 drastically promoted BMP-responsive luciferase reporter activity in a Ly294002-sensitive fashion. Both Ly294002 and DN-Akt markedly inhibited phosphorylation of Smad5 in the nuclei of brown pre-adipocytes. These results suggest that PI3K/Akt signals play a role in the GDF5-mediated brown adipogenesis through a mechanism related to activation of the Smad pathway.
Keywords:AMPK, AMP-activated protein kinase   aP2, adipocyte protein-2   BAT, brown adipose tissue   BMP, bone morphogenic protein   BMPR, bone morphogenic protein receptor   BRE-Luc, bone morphogenic protein-responsive luciferase reporter plasmid   DMEM, Dulbecco&rsquo  s modified Eagle medium   DN, dominant negative   FBS, fetal bovine serum   GAPDH, glyceraldehyde-3-phosphate dehydrogenase   GDF5, growth differentiation factor-5   HFD, high fat diet   MAPK, mitogen-activated protein kinase   PCR, polymerase chain reaction   PGC-1α, peroxisome proliferator-activated receptor gamma co-activator 1α   PI3K, phosphatidylinositol 3-kinase   Smad, mothers against decapentaplegic homolog   sWAT, subcutaneous white adipose tissue   UCP1, uncoupling protein-1   vWAT, visceral white adipose tissue   WT, wild-type
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