RESUMO
Parvin-beta is a focal adhesion protein downregulated in human breast cancer cells. Loss of Parvin-beta contributes to increased integrin-linked kinase activity, cell-matrix adhesion, and invasion through the extracellular matrix in vitro. The effect of ectopic Parvin-beta expression on the transcriptional profile of MDA-MB-231 breast cancer cells, which normally do not express Parvin-beta, was evaluated. Particular emphasis was placed upon propagating MDA-MB-231 breast cancer cells in three-dimensional culture matrices. Interestingly, Parvin-beta reexpression in MDA-MB-231 cells increased the mRNA expression, serine 82 phosphorylation (mediated by CDK9), and activity of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma), and there was a concomitant increase in lipogenic gene expression as a downstream effector of PPARgamma. Importantly, Parvin-beta suppressed breast cancer growth in vivo, with associated decreased proliferation. These data suggest that Parvin-beta might influence breast cancer progression.
Assuntos
Actinina/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Quinase 9 Dependente de Ciclina/metabolismo , PPAR gama/metabolismo , Actinina/genética , Animais , Neoplasias da Mama/genética , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Quinase 9 Dependente de Ciclina/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metabolismo dos Lipídeos , Camundongos , Transplante de Neoplasias , PPAR gama/genética , Fosforilação , Fosfosserina/metabolismo , RNA Mensageiro/genética , Transcrição Gênica/genéticaRESUMO
Resistin is an adipocyte-secreted protein that circulates at increased levels in obesity. Acute administration of resistin impairs glucose tolerance, but the effects of chronic hyperresistinemia have not been established. Here we describe the generation and characterization of transgenic mice that have high circulating levels of resistin in the setting of normal weight. Fasted blood glucose was higher in resistin-transgenic mice than in their nontransgenic littermates, and glucose tolerance was impaired in the hyperresistinemic mice. Metabolic studies in the setting of a hyperinsulinemic-euglycemic clamp protocol revealed that chronically hyperresistinemic mice have elevated glucose production. This increase in glucose production may be partly explained by increased expression of hepatic phosphoenolpyruvate carboxykinase. Thus, chronic hyperresistinemia impairs normal glucose metabolism.
Assuntos
Glicemia/metabolismo , Hormônios Ectópicos/sangue , Animais , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Homeostase , Hiperinsulinismo , Insulina/administração & dosagem , Insulina/farmacologia , Fígado/enzimologia , Camundongos , Camundongos Transgênicos , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Pré-Albumina/genética , ResistinaRESUMO
The association between obesity and diabetes supports an endocrine role for the adipocyte in maintaining glucose homeostasis. Here we report that mice lacking the adipocyte hormone resistin exhibit low blood glucose levels after fasting, due to reduced hepatic glucose production. This is partly mediated by activation of adenosine monophosphate-activated protein kinase and decreased expression of gluconeogenic enzymes in the liver. The data thus support a physiological function for resistin in the maintenance of blood glucose during fasting. Remarkably, lack of resistin diminishes the increase in post-fast blood glucose normally associated with increased weight, suggesting a role for resistin in mediating hyperglycemia associated with obesity.
Assuntos
Glicemia/metabolismo , Jejum , Hormônios Ectópicos/fisiologia , Proteínas Quinases Ativadas por AMP , Adipócitos/metabolismo , Animais , Peso Corporal , Dieta , Gorduras na Dieta/administração & dosagem , Marcação de Genes , Gluconeogênese , Teste de Tolerância a Glucose , Glucose-6-Fosfatase/metabolismo , Homeostase , Hormônios Ectópicos/administração & dosagem , Hormônios Ectópicos/sangue , Hormônios Ectópicos/genética , Insulina/sangue , Fígado/metabolismo , Masculino , Camundongos , Complexos Multienzimáticos/metabolismo , Obesidade/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Recombinantes/administração & dosagem , Resistina , Transdução de SinaisRESUMO
Obesity-associated diabetes is epidemic in industrialized societies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in adipose tissue and the presumed molecular target for antidiabetic thiazolidinedione drugs that reverse insulin resistance but also promote weight gain. Phosphorylation reduces the activity of PPARgamma in vitro, but physiological relevance has not been demonstrated. We have studied mice homozygous for a mutation (S112A) that prevents PPARgamma phosphorylation. Surprisingly, the weights and adipose mass of PPARgamma-S112A mice are not greater than wild-type. Remarkably, however, genetic prevention of PPARgamma phosphorylation preserves insulin sensitivity in the setting of diet-induced obesity. Underlying this protection are smaller fat cells, elevated serum adiponectin, and reduced free fatty acid levels. Thus, the phosphorylation state of PPARgamma modulates insulin sensitivity. Compounds that prevent PPARgamma phosphorylation or ligands that induce the conformation of nonphosphorylated PPARgamma may selectively enhance insulin sensitivity without increasing body weight.
