Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1L1376P), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.Peer reviewe

The UK10K project identifies rare variants in health and disease

M. Kivimäki työryhmäjäsen.The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7x) or exomes (high read depth, 80x) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.Peer reviewe

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume.

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development

Internações pediátricas por condições sensíveis à atenção primária em Montes Claros, Minas Gerais, Brasil Admissions to pediatric hospital for conditions amenable to primary care in Montes Claros, Minas Gerais, Brazil

OBJETIVOS: avaliar a prevalência e os fatores associados às internações pediátricas por condições sensíveis à atenção primária (CSAP). MÉTODOS: realizouse inquérito hospitalar ao longo de um ano, com amostra representativa ealeatória de crianças internadas em um município do norte de Minas Gerais. Enfermarias pediátricas foram visitadas uma vez por semana em dias diferentes. Foram investigadas variáveis demográficas, socioeconômicas e relacionadas às condições de saúde. Para a definição das afecções sensíveis a atenção primária utilizou-se a relação oficial publicada pelo Ministério da Saúde. A regressão de Poisson foi utilizada para avaliação conjunta das variáveis associadas às internações por CSAP. RESULTADOS: foram entrevistadas 365 famílias e a prevalência de internações por CSAP foi de 41,4%(n=151). O modelo final revelou que, em uma análise conjunta, as variáveis se mantiveram estatisticamente associadas com as internações por CSAP foram: residir em área da Estratégia de Saúde da Família (RP=1,19; IC95%=1,03-1,61) e idade menor que dois anos de idade (RP=1,42; IC95%=1,35-1,51). CONCLUSÕES: a prevalência observada é semelhante à encontrada em outros estudos e salienta a necessidade de melhoria dos cuidados ambulatoriais para a faixa etária estudada.<br>OBJECTIVE: to evaluate the prevalence and factors associated with admission to pediatric hospital for conditions amenable to primary care. METHODS: an investigation was carried out for the duration of one year, with a representative sample of children admitted to hospital in a municipality in thenorth of the Brazilian State of Minas Gerais. Pediatric wards were visited once a week on different days. Demographic, socio-economic and health variables were studied. Conditions amenable to primary care were established using the official report published by the Brazilian Ministry of Health. The Poisson regression was used to evaluate the set of variables associated with admission to hospital for conditions amenable to primary care. RESULTS: 365 families were interviewed and the prevalence of admission to hospital for conditions amenable to primary care was 41.4% (n=151). Thefinal model revealed that, when taken together, the variables that continued to be associated in a statistically significant fashion with admissions to hospital for conditions amenable to primary care were: living in a Family Health Strategy area (PR=1.19;CI95%=1.039-1.61) and being aged under two years(PR=1.42; CI95%=1.35-1.51). CONCLUSION: the prevalence observed is similar to that found by other studies and highlights the need to improve out patient care for the age group covered by this study