Knockdown of SF-1 and RNF31 Affects Components of Steroidogenesis, TGFβ, and Wnt/β-catenin Signaling in Adrenocortical Carcinoma Cells

The orphan nuclear receptor Steroidogenic Factor-1 (SF-1, NR5A1) is a critical regulator of development and homeostasis of the adrenal cortex and gonads. We recently showed that a complex containing E3 ubiquitin ligase RNF31 and the known SF-1 corepressor DAX-1 (NR0B1) interacts with SF-1 on target promoters and represses transcription of steroidogenic acute regulatory protein (StAR) and aromatase (CYP19) genes. To further evaluate the role of SF-1 in the adrenal cortex and the involvement of RNF31 in SF-1-dependent pathways, we performed genome-wide gene-expression analysis of adrenocortical NCI-H295R cells where SF-1 or RNF31 had been knocked down using RNA interference. We find RNF31 to be deeply connected to cholesterol metabolism and steroid hormone synthesis, strengthening its role as an SF-1 coregulator. We also find intriguing evidence of negative crosstalk between SF-1 and both transforming growth factor (TGF) β and Wnt/β-catenin signaling. This crosstalk could be of importance for adrenogonadal development, maintenance of adrenocortical progenitor cells and the development of adrenocortical carcinoma. Finally, the SF-1 gene profile can be used to distinguish malignant from benign adrenocortical tumors, a finding that implicates SF-1 in the development of malignant adrenocortical carcinoma

Statin modulates insulin signaling and insulin resistance in liver and muscle of rats fed a high-fat diet

Recent studies have shown that statins might have relevant effects on insulin resistance in animal models and in humans. However, the molecular mechanisms that account for this improvement in insulin sensitivity are not well established. The aim of the present study was to investigate the effect of a statin on insulin sensitivity and insulin signaling in liver and muscle of rats fed on a high-fat diet (HFD) for 4 weeks, treated or not with lovastatin during the last week. Our data show that treatment with lovastatin results in a marked improvement in insulin sensitivity characterized by an increase in glucose disappearance rate during the insulin tolerance test. This increase in insulin sensitivity was associated with an increase in insulin-induced insulin receptor (IR) tyrosine phosphorylation and, in parallel, a decrease in IR serine phosphorylation and association with PTP1B. Our data also show that lovastatin treatment was associated with an increase in insulin-stimulated insulin receptor substrate (IRS) 1/phosphatidylinositol 3-kinase/Akt pathway in the liver and muscle of HFD-fed rats in parallel with a decrease in the inflammatory pathway (c-jun N-terminal kinase and 1 kappa beta kinase (IKK beta/inhibitor of kappa B/nuclear factor kappa B) related to insulin resistance. In summary,, statin treatment improves insulin sensitivity in HFD-fed rats by reversing the decrease in the insulin-stimulated IRS-1/phosphatidylinositol 3-kinase/Akt pathway in liver and muscle. The effect of statins on insulin action is further supported by our findings that HFD rats treated with statin show a reduction in IRS-1 serine phosphorylation, I kappa kinase (IKK)/inhibitor of kappa B/ nuclear factor kappa B pathway, and c-jun N-terminal kinase activity, associated with an improvement in insulin action. Overall, these results provide important new insight into the mechanism of statin action in insulin sensitivity. (C) 2008 Elsevier Inc. All rights reserved.571576

Prevalência de obesidade em crianças de uma escola pública e de um ambulatório geral de Pediatria de hospital universitário Obesity prevalence among students of a public school and a Pediatric out-patient clinic of a university hospital

OBJETIVO: Verificar a associação entre atividade física e características socioeconômicas com a presença de obesidade e/ou sobrepeso em crianças de seis a 14 anos, escolares da Escola Sérgio Porto e pacientes que procuraram o Ambulatório de Pediatria no Hospital de Clínicas (HC), ambos no campus da Universidade Estadual de Campinas (Unicamp). MÉTODOS: O estudo foi realizado por meio da aplicação de questionário aos pais ou responsáveis e coleta de dados de peso e altura das crianças. Foi calculado o índice de massa corpórea (IMC), e feita a classificação em normal, sobrepeso ou obesidade, a partir dos dados do Centers for Disease Control and Prevention (CDC), dos Estados Unidos. Foi feita análise descritiva dos dados e utilizados os testes do qui-quadrado ou exato de Fisher. RESULTADOS: A amostra ambulatorial foi composta por 107 crianças (13,1% com sobrepeso e 11,2% obesas) e a escolar de 109 (16,5% com sobrepeso e 20,2% obesas). Não foi observada diferença significante entre a prevalência de obesidade ou de obesidade e sobrepeso entre as duas amostras, apesar de as amostras serem diferentes em relação à renda mensal (p<0,0001), escolaridade materna (p<0,0001) e atividade física (p<0,0001), sendo que a população ambulatorial apresentou menores índices nestas três variáveis, comparada à escolar. CONCLUSÕES: Os índices de sobrepeso e obesidade encontrados no presente estudo foram elevados, confirmando que houve a transição nutricional em ambas as amostras, de maneira similar à observada no resto do nosso país, independentemente do sexo, da classificação socioeconômica e da atividade física.<br>OBJECTIVE: The aim of this study was to verify the association between physical activity and socio-economic status with the presence of obesity and/or overweight in children aged six to 14 years of two different sources: an elementary school and an out-patient Pediatric clinic of one university hospital of Campinas, São Paulo. METHODS: A socio-demographic questionnaire was answered by parents and the evaluation of children's weight and height was performed according to Centers for Disease Control and Prevention (CDC), USA, standards for body mass index (BMI) The children were divided in three categories: normal, overweight and obese. Chi-square and Fisher exact test were used to compare both groups of children. RESULTS: 107 children from the university hospital were studied (13.1% with overweight and 11.2% obese) as well as 109 from the elementary school (16.5% overweight and 20.2% obese). Both groups were similar regarding the prevalence of obesity alone or obesity and overweight. Groups differed in family income (p<0.0001), number of maternal years in school (p<0.0001) and physical activity (p<0.0001), with disadvantage of the clinic patients. CONCLUSIONS: The frequency of overweight and obesity observed in this study were high, pointing out that a nutritional transition has occurred in both samples independently of gender, socio-economic status and physical activity

Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice

Spermiogenesis is a complex process by which postmeiotic male germ cells differentiate into mature spermatozoa. This process involves remarkable structural and biochemical changes including nuclear DNA compaction and acrosome formation(1,2). Transcriptional activator CREM (cyclic AMP-responsive element modulator) is highly expressed in postmeiotic cells(3-5), and CREM may be responsible for the activation of several haploid germ cell-specific genes involved in the structuring of the spermatozoon(5-7). The specific role of CREM in spermiogenesis was addressed using CREM-mutant mice generated by homologous recombination. Analysis of the seminiferous epithelium in mutant male mice reveals postmeiotic arrest at the first step of spermiogenesis. Late spermatids are completely absent, and there is a significant increase in apoptotic germ cells. We show that CREM deficiency results in the lack of postmeiotic cell-specific gene expression. The complete lack of spermatozoa in the mutant mice is reminiscent of cases of human infertility