RESUMO
Adipose (Adp) is an evolutionarily conserved gene isolated from naturally occurring obese flies homozygous for an adp mutation. Here we show that the anti-obesity function of Adp (worm Y73E7A.9, fly adp, and murine Wdtc1) is conserved from worms to mammals. Further, Adp appears to inhibit fat formation in a dosage-sensitive manner. Adp heterozygous flies and Adp heterozygous mutant mice are obese and insulin resistant, as are mice that express a dominant negative form of Adp in fat cells. Conversely, fat-restricted Adp transgenic mice are lean and display improved metabolic profiles. A transient transgenic increase in Adp activity in adult fly fat tissues reduces fat accumulation, indicating therapeutic potential. ADP may elicit these anti-adipogenic functions by regulating chromatin dynamics and gene transcription, as it binds both histones and HDAC3 and inhibits PPARgamma activity. Thus Adp appears to be involved in an ancient pathway that regulates fat accumulation.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Obesidade/genética , Proteínas/genética , Proteínas/metabolismo , Tecido Adiposo/anatomia & histologia , Tecido Adiposo/fisiologia , Animais , Caenorhabditis elegans/anatomia & histologia , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/antagonistas & inibidores , Proteínas de Drosophila/antagonistas & inibidores , Feminino , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/prevenção & controle , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Obesidade/prevenção & controle , Proteínas/antagonistas & inibidoresRESUMO
Hedgehog (Hh) signals regulate invertebrate and vertebrate development, yet the role of the cascade in adipose development was undefined. To analyze a potential function, we turned to Drosophila and mammalian models. Fat-body-specific transgenic activation of Hh signaling inhibits fly fat formation. Conversely, fat-body-specific Hh blockade stimulated fly fat formation. In mammalian models, sufficiency and necessity tests showed that Hh signaling also inhibits mammalian adipogenesis. Hh signals elicit this function early in adipogenesis, upstream of PPARgamma, potentially diverting preadipocytes as well as multipotent mesenchymal prescursors away from adipogenesis and toward osteogenesis. Hh may elicit these effects by inducing the expression of antiadipogenic transcription factors such as Gata2. These data support the notion that Hh signaling plays a conserved role, from invertebrates to vertebrates, in inhibiting fat formation and highlighting the potential of the Hh pathway as a therapeutic target for osteoporosis, lipodystrophy, diabetes, and obesity.