Xanthine oxidoreductase is a regulator of adipogenesis and PPARgamma activity.
In an effort to identify novel candidate regulators of adipogenesis, gene profiling of differentiating 3T3-L1 preadipocytes was analyzed using a novel algorithm. We report here the characterization of xanthine oxidoreductase (XOR) as a novel regulator of adipogenesis. XOR lies downstream of C/EBPbeta and upstream of PPARgamma, in the cascade of factors that control adipogenesis, and it regulates PPARgamma activity. In vitro, knockdown of XOR inhibits adipogenesis and PPARgamma activity while constitutive overexpression increases activity of the PPARgamma receptor in both adipocytes and preadipocytes. In vivo, XOR -/- mice demonstrate 50% reduction in adipose mass versus wild-type littermates while obese ob/ob mice exhibit increased concentrations of XOR mRNA and urate in the adipose tissue. We propose that XOR is a novel regulator of adipogenesis and of PPARgamma activity and essential for the regulation of fat accretion. Our results identify XOR as a potential therapeutic target for metabolic abnormalities beyond hyperuricemia.
Cheung
Kevin J
KJ
Laboratory of Molecular Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Tzameli
Iphigenia
I
Pissios
Pavlos
P
Rovira
Ilsa
I
Gavrilova
Oksana
O
Ohtsubo
Toshio
T
Chen
Zhu
Z
Finkel
Toren
T
Flier
Jeffrey S
JS
Friedman
Jeffrey M
JM
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D050156:Adipogenesis / Q000187:drug effects; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014968:Xanthine Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D022763:CCAAT-Enhancer-Binding Protein-alpha; D047495:PPAR gamma; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D014968:Xanthine Dehydrogenase