Ginkgo biloba Extract (GbE) Stimulates the Hypothalamic Serotonergic System and Attenuates Obesity in Ovariectomized Rats

Menopause is associated with increased risk to develop obesity but the mechanisms involved are not fully understood. We have shown that Ginkgo biloba extract (GbE) improved diet-induced obesity. Since GbE might be effective in the treatment of obesity related to menopause, avoiding the side effects of hormone replacement therapy, we investigated the effect of GbE on hypothalamic systems controlling energy homeostasis. Wistar rats were either ovariectomized (OVX) or Sham-operated. After 2 months, either 500 mg.kg(-1) of GbE or vehicle were administered daily by gavage for 14 days. A subset of animals received an intracerebroventricular (i.c.v.) injection of serotonin (300 mu g) or vehicle and food intake was measured after 12 and 24 h. Another subset was submitted to in vivo microdialysis and 5-HT levels of the medial hypothalamus were measured by high performance liquid chromatography, before and up to 2 h after the administration of 500 mg.kg(-1) of GbE. Additional animals were used for quantification of 5-HT1A, 5-HT1B, 5-HT2C, 5-HTT, and pro-opiomelanocortin hypothalamic protein levels by Western blotting. OVX increased food intake and body weight and adiposity while GbE attenuated these alterations. i.c.v. serotonin significantly reduced food intake in Sham, Sham + GbE, and OVX + GbE groups while it failed to do so in the OVX group. In the OVX rats, GbE stimulated 5-HT microdialysate levels while it reduced hypothalamic 5-HTT protein levels. The results indicate that GbE improved the ovariectomy-induced resistance to serotonin hypophagia, at least in part through stimulation of the hypothalamic serotonergic activity. Since body weight gain is one of the most important consequences of menopause, the stimulation of the serotonergic transmission by GbE may represent a potential alternative therapy for menopause-related obesity.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Univ Fed Sao Paulo, Dept Fisiol, Disciplina Fisiol Nutr, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Ciencias Biol, Setor Morfofisiol & Patol, Diadema, BrazilUniv Fed Sao Paulo, Dept Fisiol, Disciplina Fisiol Nutr, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Ciencias Biol, Setor Morfofisiol & Patol, Diadema, BrazilCNPq: 453924/2014-0FAPESP: 2012/03172-4FAPESP: 2014/18435-6Web of Scienc

Effect of fish oil intake on glucose levels in rat prefrontal cortex, as measured by microdialysis

Background: Brain glucose sensing may contribute to energy homeostasis control. the prefrontal cortex (PFC) participates in the hedonic component of feeding control. As high-fat diets may disrupt energy homeostasis, we evaluated in male Wistar rats whether intake of high-fat fish-oil diet modified cortical glucose extracellular levels and the feeding induced by intracerebroventricular glucose or PFC glucoprivation.Methods: Glucose levels in PFC microdialysates were measured before and after a 30-min meal. Food intake was measured in animals receiving intracerebroventricular glucose followed, 30-min. later, by 2-deoxy-D-glucose injected into the PFC.Results: the fish-oil group showed normal body weight and serum insulin while fat pads weight and glucose levels were increased. Baseline PFC glucose and 30-min. carbohydrates intake were similar between the groups. Feeding-induced PFC glucose levels increased earlier and more pronouncedly in fish-oil than in control rats. Intracerebroventricular glucose inhibited feeding consistently in the control but not in the fish-oil group. Local PFC glucoprivation with 2-DG attenuated glucose-induced hypophagia.Conclusions: the present experiments have shown that, following food intake, more glucose reached the prefrontal cortex of the rats fed the high-fat fish-oil diet than of the rats fed the control diet. However, when administered directly into the lateral cerebral ventricle, glucose was able to consistently inhibit feeding only in the control rats. the findings indicate that, an impairment of glucose transport into the brain does not contribute to the disturbances induced by the high-fat fish-oil feeding.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo Unifesp, Dept Fisiol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo Unifesp, Dept Fisiol, BR-04023062 São Paulo, BrazilWeb of Scienc

Lateral hypothalamic serotonin is not stimulated during central leptin hypophagia

Whether leptin targets the hypothalamic serotonergic system to inhibit food intake is not established. We examined the effect of a short-term i.c.v. leptin treatment on serotonin microdialysate levels in rat lateral hypothalamus. Adipose tissue gene expression was also evaluated.Male rats received four daily injections of leptin (5 mu g) or vehicle (with pair-feeding to leptin-induced intake) and a fifth injection during collection of LH microdialysates. We found that serotonin and 5-HIAA levels were not affected by the leptin pre-treatment, as basal levels were similar between the leptin and the pair-fed group. These levels remained unaltered after the acute leptin injection.For gene expression studies, rats were pre-treated with five daily injections of either leptin (5 mu g) or vehicle (with either pair-feeding or ad libitum intake). mRNA levels of resistin, adiponectin, lipoprotein lipase, and PPAR-gamma were unaltered by either leptin or pair-feeding. Leptin gene expression was significantly reduced by leptin but not by pair-feeding, in both the retroperitoneal (- 74%) and the epididymal (- 99%) depots while no differences were observed in the subcutaneous depot.The observations confirmed the absence of an acute stimulatory effect of central leptin on serotonin release in the lateral hypothalamus and showed that the pre-treatment with leptin failed to modify this pattern. This indicates that components of the serotonergic system are probably not directly affected by leptin. Additionally, the central effect of leptin was able to downregulate its own adipose tissue gene expression in a depot-specific manner while other adipokine genes were not affected. (C) 2013 Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo, UNIFESP, Dept Fisiol, Disciplina Fisiol Nutr, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Ciencias Biol, Diadema, SP, BrazilUniversidade Federal de São Paulo, UNIFESP, Dept Fisiol, Disciplina Fisiol Nutr, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Ciencias Biol, Diadema, SP, BrazilWeb of Scienc

L-arginine abolishes the hypothalamic serotonergic activation induced by central interleukin-1 beta administration to normal rats

IL-1 beta-induced anorexia may depend on interactions of the cytokine with neuropeptides and neurotransmitters of the central nervous system control of energy balance and serotonin is likely to be one catabolic mediator targeted by IL-1 beta. in the complex interplay involved in feeding modulation, nitric oxide has been ascribed a stimulatory action, which could be of significance in counteracting IL-1 beta effects.The present study aims to explore the participation of the nitric oxide and the serotonin systems on the central mechanisms induced by IL-1 beta and the relevance of their putative interactions to IL-1 beta hypophagia in normal rats. Serotonin levels were determined in microdialysates of the ventromedial hypothalamus after a single intracerebroventricular injection of 10 ng of IL-1 beta, with or without the pre-injection of 20 mu g of the nitric oxide precursor L-arginine. IL-1 beta significantly stimulated hypothalamic serotonin extracellular levels, with a peak variation of 130 +/-37% above baseline. IL-1 beta also reduced the 4-h and the 24-h food intakes (by 23% and 58%, respectively). the IL-1 beta-induced serotonergic activation was abolished by the pre-injection of L-arginine while the hypophagic effect was unaffected.The data showed that one central effect of IL-1 beta is serotonergic stimulation in the ventromedial hypothalamus, an action inhibited by nitric oxide activity. It is suggested that, although serotonin participates in IL-1 beta anorexia, other mechanisms recruited by IL-1 beta in normal rats are able to override the absence of the serotonergic hypophagic influence.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Physiol, BR-04023060 São Paulo, BrazilUniversidade Federal de São Paulo, Div Appl Stat, BR-04023060 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Physiol, BR-04023060 São Paulo, BrazilUniversidade Federal de São Paulo, Div Appl Stat, BR-04023060 São Paulo, BrazilWeb of Scienc

Beneficial effects of Ginkgo biloba extract on insulin signaling cascade, dyslipidemia, and body adiposity of diet-induced obese rats

Ginkgo biloba extract (GbE) has been indicated as an efficient medicine for the treatment of diabetes mellitus type 2. It remains unclear if its effects are due to an improvement of the insulin signaling cascade, especially in obese subjects. The aim of the present study was to evaluate the effect of GbE on insulin tolerance, food intake, body adiposity, lipid profile, fasting insulin, and muscle levels of insulin receptor substrate 1 (IRS-1), protein tyrosine phosphatase 1B (PTP-1B), and protein kinase B (Akt), as well as Akt phosphorylation, in diet-induced obese rats. Rats were fed with a high-fat diet (HFD) or a normal fat diet (NFD) for 8 weeks. After that, the HFD group was divided into two groups: rats gavaged with a saline vehicle (HFD+V), and rats gavaged with 500 mg/kg of GbE diluted in the saline vehicle (HFD+Gb). NFD rats were gavaged with the saline vehicle only. At the end of the treatment, the rats were anesthetized, insulin was injected into the portal vein, and after 90s, the gastrocnemius muscle was removed. The quantification of IRS-1, Akt, and Akt phosphorylation was performed using Western blotting. Serum levels of fasting insulin and glucose, triacylglycerols and total cholesterol, and LDL and HDL fractions were measured. An insulin tolerance test was also performed. Ingestion of a hyperlipidic diet promoted loss of insulin sensitivity and also resulted in a significant increase in body adiposity, plasma triacylglycerol, and glucose levels. In addition, GbE treatment significantly reduced food intake and body adiposity while it protected against hyperglycemia and dyslipidemia in diet-induced obesity rats. It also enhanced insulin sensitivity in comparison to HFD+V rats, while it restored insulin-induced Akt phosphorylation, increased IRS-1, and reduced PTP-1B levels in gastrocnemius muscle. The present findings suggest that G. biloba might be efficient in preventing and treating obesity-induced insulin signaling impairment.Universidade Federal de São Paulo (UNIFESP) Departamento de Ciências BiológicasUniversidade Federal de São Paulo (UNIFESP) Departamento de Fisiologia Disciplina de Fisiologia da NutriçãoUniversidade Federal de São Paulo (UNIFESP) Departamento de BiociênciasUniversidade Federal de Alagoas Faculdade de NutriçãoUniversidade Federal do Rio de Janeiro Curso de NutriçãoUNIFESP, Depto. de Ciências BiológicasUNIFESP, Depto. de Fisiologia Disciplina de Fisiologia da NutriçãoUNIFESP, Depto. de BiociênciasSciEL

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Central end peripheral effects of repeated leptin treatment in normal rats

O hormônio adipocitário leptina exerce um papel fundamental na manutenção da homeostase energética, promovendo redução tanto da ingestão alimentar como da massa corporal. Diversos estudos indicam que o efeito anorexígeno da leptina decorre de sua ação sobre circuitos centrais envolvidos no controle do balanço energético. Entretanto, os mecanismos pelos quais a leptina exerce suas ações centrais ainda não se encontram totalmente elucidados. O presente estudo teve como um de seus objetivos avaliar se a leptina exerce seu efeito anorexígeno via ativação do sistema serotonérgico. Ratos Wistar normais foram tratados com 4 injeções i.c.v. diárias de 5μg ou lOμg de leptina (grupos Lep5 e LeplO) ou pré-tratados com veículo e acesso à alimentação pareada aos respectivos grupos tratados (PF5 e PF10). No quinto dia, os animais permaneceram em jejum e amostras de dialisato foram coletadas do hipotálamo lateral. Durante o experimento de microdiálise, todos os grupos receberam uma injeção aguda de veículo seguida, uma hora depois, de uma injeção aguda de leptina. o pré-tratamento com leptina i.c.v. promoveu redução significante da ingestão alimentar. Observamos que esta redução ocorreu de forma dose-dependente, já que em relação ao grupo Lep5, o grupo Lep10 apresentou redução significante do consumo alimentar nos dias 3 e 4 de pré-tratamento. Os níveis basais de serotonina (5-HT) hipotalâmica foram semelhantes entre os grupos, ao passo que os níveis de ácido 5-hidroxindolacético (5-HIAA) foram mais baixos nos grupos PF10 e Lep10. Tanto no grupo PF5 como no Lep5, os níveis de 5-HT permaneceram estáveis após a injeção de veículo ou leptina, enquanto os níveis de 5¬HIAA aumentaram, indicando um aumento da síntese de 5-HT. Os grupos PF10 e Lep 10 apresentaram respostas diferentes ao tratamento. No grupo PF10, os níveis de 5-HT caíram logo após a injeção do veículo sendo que a dose aguda de leptina não modificou este efeito. Por outro lado, as injeções agudas tanto de veículo como de leptina não promoveram alteração dos níveis de 5-HT no grupo Lep10. Os níveis de 5-HIAA permaneceram inalterados no grupo PF10 ao passo que aumentaram no grupo Lep 10. Estes dados indicam que o tratamento agudo com leptina, por si só, não promoveu um efeito estimulador direto sobre a liberação hipotalâmica de serotonina e que este padrão não foi modificado pelo pré-tratamento com a proteína. Contudo, numa situação de diminuição da atividade serotonérgica, como a decorrente de restrição alimentar drástica, o pré-tratamento com leptina preveniu a queda dos níveis hipotalâmicos de serotonina, provavelmente por estimular a síntese de 5-HT. É possível que, ao invés de agir diretamente sobre a transmissão serotonérgica, a leptina se contraponha aos fatores que levam à inibição serotonérgica após uma restrição alimentar. Este efeito poderia ser uma das vias pelas quais a leptina promove redução da ingestão alimentar. O segundo objetivo do presente estudo foi avaliar se a leptina, ao agir no sistema nervoso central, afeta a expressão gênica de adipocinas. Para isto, utilizamos a técnica de Northern Blotting para avaliar a expressão gênica de leptina, adiponectina, PPARγ, resistina e LPL em amostras de tecido adiposo branco epididimal, retroperitoneal e subcutâneo, provenientes de animais dos grupos PF5, Lep5 e AL (ad libitum - tratados com CSF e com livre acesso ao alimento). O tratamento com leptina i.c.v. reduziu sua própria expressão nos depósitos de tecido adiposo branco epididimal e retroperitoneal. Observamos que este efeito ocorreu de forma depósito-dependente já que o tratamento não modificou a expressão de leptina no depósito subcutâneo. Por outro lado, a expressão gênica das demais adipocinas nos três depósitos de tecido adiposo analisados não foi modificada pelo tratamento. Nossos dados sugerem que ao agir centralmente, a leptina é capaz de controlar a sua própria expressão por meio de retroalimentação negativa. Contudo, nossos resultados indicam que as ações centrais da leptina não afetam a expressão gênica de adiponectina, PPARγ, resistina e LPL. É possível que doses mais elevadas de leptina promovam alteração da expressão gênica destas adipocinas.BV UNIFESP: Teses e dissertaçõe