An Intestinal FXR Agonist Mitigates Dysbiosis, Intestinal Tight Junctions, and Inflammation in High-Fat Diet-Fed Mice.

SCOPE: To analyze the effects of fexaramine (FEX), as an intestinal FXR agonist, on the modulation of the intestinal microbiota and ileum of mice fed a high-fat (HF) diet. METHODS AND RESULTS: Three-month-old C57Bl/6 male mice are divided into two groups and received a control (C, 10% of energy from lipids) or HF (50% of energy from lipids) diet for 12 weeks. They are subdivided into the C, C + FEX, HF, and HF + FEX groups. FEX is administered (FEX-5 mg kg-1 ) via orogastric gavage for three weeks. Body mass (BM), glucose metabolism, qPCR 16S rRNA gene expression, and ileum gene expression, bile acids (BAs), tight junctions (TJs), and incretin are analyzed. FEX reduces BM and glucose intolerance, reduces plasma lipid concentrations and the Firmicutes/Bacteroidetes ratio, increases the Lactobacillus sp. and Prevotella sp. abundance, and reduces the Escherichia coli abundance. Consequently, the ileal gene expression of Fxr-Fgf15, Tgr5-Glp1, and Cldn-Ocldn-Zo1 is increased, and Tlr4-Il6-Il1beta is decreased. CONCLUSION: FEX stimulates intestinal FXR and improves dysbiosis, intestinal TJs, and the release of incretins, mitigating glucose intolerance and BM increases induced by an HF diet. However, FEX results in glucose intolerance, insulin resistance, and reduces intestinal TJs in a control group, thus demonstrating limitations to this dietary model.

Psychosocial adjustment profiles of Elementary School 6th graders: a Cluster-based analysis / Perfis de ajustamento psicossocial de estudantes do 6º ano do Ensino Fundamental: uma análise baseada em Clusters

Based on the resilience theory, this study aimed to analyze different psychosocial adjustment profiles of Elementary School 6th graders, considering risk factors (school stressors and daily discrimination), protection (social skills, family support, and school climate) and adjustment indicators (general and academic self-efficacy beliefs). A total of 448 students (between 10 and 17 years old) from public schools in the state of Rio de Janeiro (Brazil) participated. Through cluster analysis, two profiles were identified: resilient, with high levels of risk indicators and good adjustment; and vulnerable, with high levels of risk and low adjustment. The results indicated that the protective factors do not neutralize the stressful psychophysiological phenomena associated with the transition, but they mitigate the impact of the risk, increasing the coping capacity in the new context, promoting students' resilience.

Fundamentado na teoria da resiliência, este estudo teve por objetivo analisar diferentes perfis de ajustamento psicossocial de estudantes do 6º ano do Ensino Fundamental. Foram considerados fatores de risco (estressores escolares e discriminação cotidiana), proteção (habilidades sociais, suporte familiar e clima escolar) e indicadores de ajustamento (crenças de autoeficácia geral e acadêmica). Participaram 448 alunos, com idade entre 10 e 17 anos, de escolas públicas do Estado do Rio de Janeiro (Brasil). Por meio da análise de clusters, dois perfis foram identificados: resiliente, com valores altos de indicadores de risco com bom ajustamento, e vulnerável, com índices altos de risco e baixo ajustamento. Os resultados indicaram que os fatores de proteção não anulam os fenômenos psicofisiológicos estressantes associados à transição, mas amortizam o impacto do risco, aumentando a capacidade de enfrentamento diante do novo contexto, promovendo a resiliência dos alunos.

Transición Escolar en los Años Finales de la Enseñanza Básica: Revisión Integrativa de la Literatura / Transição escolar nos anos finais do ensino fundamental: revisão integrativa da literatura / Transition in the final years of elementary school: integrative review on the literature

A transição escolar no Ensino Fundamental interessa a pesquisadores do desenvolvimento, que buscam identificar seus efeitos no ajustamento escolar, intra e interpessoal dos alunos. Com o objetivo de mapear a produção científica acerca das repercussões da transição escolar dos anos iniciais para finais do Ensino Fundamental sobre o desenvolvimento socioemocional e acadêmico dos estudantes, realizou-se revisão integrativa da literatura, desde 2013 a junho de 2018, nos bancos de dados SciELO, PsycINFO, ERIC e Science Direct. Mediante critérios de inclusão e exclusão foram incorporados e analisados na perspectiva de proteção/risco ao desenvolvimento 30 artigos. A maioria dos estudos investigou fatores de proteção/risco conjuntamente, com predominância de fatores protetivos contextuais. Os desfechos positivos se sobressaíram na transição para os anos finais do Ensino Fundamental. A perspectiva de risco/proteção se mostrou pertinente para integração dos resultados, evidenciando que a transição escolar é um fenômeno dinâmico e multifacetado.

La transición escolar en la Enseñanza Básica interesa a investigadores del desarrollo, que buscan identificar sus efectos en el ajustamiento escolar, intra e interpersonal de los alumnos. Con el objetivo de mapear la producción científica acerca de las repercusiones de la transición escolar de los años iniciales para finales de la Enseñanza Básica sobre el desarrollo socioemocional y académico de los estudiantes, se realizó revisión integrativa de la literatura, desde 2013 a junio de 2018, en los bancos de datos SciELO, PsycINFO, ERIC y Science Direct. Por intermedio de criterios de inclusión y exclusión fueron incorporados y analizados en la perspectiva de protección/riesgo al desarrollo 30 artículos. Gran parte de los estudios investigó factores de protección/riesgo conjuntamente, con predominancia de factores de protección contextuales. Los resultados positivos se sobresalen en la transición a los años finales de la Enseñanza Básica. La perspectiva de riesgo/protección se mostró pertinente para integración de los resultados, evidenciando que la transición escolar es un fenómeno dinámico y multifacético.

The theme of transition in Elementary School is of interest to development researchers, who seek to identify its effects on students' intra- and interpersonal school adjustment. In order to map out the scientific production on the repercussions of the transition from the early to the late years of Elementary School on the students' socio-emotional and academic development, an integrative literature review was carried out, from 2013 to June 2018, in the SciELO, PsycINFO, ERIC and Science Direct databases. Through inclusion and exclusion criteria, 30 articles were incorporated and analyzed from the perspective of protection/risk to development. Most studies investigated protective/risk factors together, with a predominance of contextual protective factors. Positive outcomes stood out in the transition to the final years of elementary school. The risk/protection perspective proved to be relevant for the integration of results, showing that school transition is a dynamic and multifaceted phenomenon.

Ovariectomy modify local renin-angiotensin-aldosterone system gene expressions in the heart of ApoE (-/-) mice.

AIMS: The evaluation of the local Renin-Angiotensin-Aldosterone system (RAAS) gene expressions in the heart of ovariectomized (OVX) apolipoprotein E deficient mice (ApoE). METHODS: Four-months old C57BL/6 female mice (wild-type, wt, n=20), and ApoE female mice (n=20), were submitted to OVX or a surgical procedure without ovary removal (SHAM) and formed four groups (n=10/group): SHAM/wt, SHAM/ApoE, OVX/wt, and OVX/ApoE. KEY FINDINGS: OVX led to greater body mass, plasma triglycerides (TG) and total cholesterol, and resulted in insulin resistance and altered RAAS gene expressions in the heart tissue. The gene expression of angiotensin-converting enzyme (ACE)-2 was lower in OVX/wt than in SHAM/wt (P=0.0004), Mas receptor (MASr) was lower in OVX/wt compared to SHAM/wt (P<0.0001). Also, angiotensin II receptor type 1 (AT1r) was higher in OVX/wt than in SHAM/wt (P=0.0229), and AT2r was lower in OVX/wt than in SHAM/wt (P=0.0121). OVX and ApoE deficiency showed interaction potentializing the insulin resistance, increasing TG levels and altering ACE and MASr gene expressions. ACE gene expression was higher in OVX/ApoE than in OVX/wt (P<0.0001), and MASr gene expression was lower in OVX/ApoE than in OVX/wt (P<0.0001). SIGNIFICANCE: The impact of OVX on local RAAS cascade in the heart of ApoE deficient animals, besides the metabolic changes culminating with insulin resistance, involves an upregulation of renin, ACE, and AT1r gene expressions. The findings may contribute to clarify the mechanisms of development of postmenopausal hypertension and the link between RAAS and apolipoprotein E.

PPAR-α agonist elicits metabolically active brown adipocytes and weight loss in diet-induced obese mice.

Obesity is considered a public health problem worldwide. Fenofibrate, a selective peroxisome proliferator-activated receptor α (PPAR-α) agonist, elicits weight loss in animal models. This study aimed to examine the effects of fenofibrate on energy expenditure, body mass (BM) and gene expression of thermogenic factors in brown adipose tissue of diet-induced obese mice. Male C57BL/6 mice were fed a standard chow (SC; 10% lipids) diet or a high-fat (HF; 50% lipids) diet for 10 weeks. Afterwards, groups were subdivided as SC, SC-F, HF and HF-F (n = 10, each). Treatment with fenofibrate (100 mg kg(-1) BM mixed into the diet) lasted 5 weeks. Treated groups had reduced final BM compared with their counterparts (p < 0·05), explained by the increase in energy expenditure, CO2 production and O2 consumption after treatment with fenofibrate (p < 0·05). Similarly, genes involved in thermogenesis as PPAR-α, PPAR-γ coactivator 1α, nuclear respiratory factor 1, mitochondrial transcription factor A (Tfam), PR domain containing 16 (PRDM16), ß-3 adrenergic receptor (ß3-AR), bone morphogenetic protein 8B and uncoupling protein 1 were significantly expressed in brown adipocytes after the treatment (p < 0·05). All observations ensure that selective PPAR-α agonist can induce thermogenesis by increasing energy expenditure and enhancing the expression of genes involved in the thermogenic pathway. These results suggest fenofibrate as a coadjutant drug for the treatment of obesity.

Short-term administration of GW501516 improves inflammatory state in white adipose tissue and liver damage in high-fructose-fed mice through modulation of the renin-angiotensin system.

High activation of the angiotensin-converting enzyme (ACE)/(angiotensin-II type 1 receptor) AT1r axis is closely linked to pro-inflammatory effects and liver damage. The aim of this study was to evaluate the effects of the short-term administration of GW501516 on pro-inflammatory markers in white adipose tissue (WAT) and hepatic stellate cells (HSCs), lipogenesis and insulin resistance in the liver upon high-fructose diet (HFru)-induced ACE/AT1r axis activation. Three-month-old male C57Bl/6 mice were fed a standard chow diet or a HFru for 8 weeks. Then, the animals were separated randomly into four groups and treated with GW501516 for 3 weeks. Morphological variables, systolic blood pressure, and plasma determinations were analyzed. In the WAT, the ACE/AT1r axis and pro-inflammatory cytokines were assessed, and in the liver, the ACE/AT1r axis, HSCs, fatty acid oxidation, insulin resistance, and AMPK activation were evaluated. The HFru group displayed a high activation of the ACE/AT1r axis in both the WAT and liver; consequently, we detected inflammation and liver damage. Although GW501516 abolished the increased activation of the ACE/AT1r axis in the WAT, no differences were found in the liver. GW501516 blunted the inflammatory state in the WAT and reduced HSC activation in the liver. In addition, GW501516 alleviates damage in the liver by increasing the expression of the genes that regulate beta-oxidation and decreasing the expression of the genes and proteins that are involved in lipogenesis and gluconeogenesis. We conclude that GW501516 may serve as a therapeutic option for the treatment of a highly activated ACE/AT1r axis in WAT and liver.

Fenofibrate (PPARalpha agonist) induces beige cell formation in subcutaneous white adipose tissue from diet-induced male obese mice.

Browning is characterized by the formation of beige/brite fat depots in subcutaneous white adipose tissue (sWAT). This study aimed to examine whether the chronic activation of PPARalpha by fenofibrate could induce beige cell depots in the sWAT of diet-induced obese mice. High-fat fed animals presented overweight, insulin resistance and displayed adverse sWAT remodeling. Fenofibrate significantly attenuated these parameters. Treated groups demonstrated active UCP-1 beige cell clusters within sWAT, confirmed through higher gene expression of PPARalpha, PPARbeta, PGC1alpha, BMP8B, UCP-1, PRDM16 and irisin in treated groups. PPARalpha activation seems to be pivotal to trigger browning through irisin induction and UCP-1 transcription, indicating that fenofibrate increased the expression of genes typical of brown adipose tissue (BAT) in the sWAT, characterizing the formation of beige cells. These findings put forward a possible role of PPARalpha as a promising therapeutic for metabolic diseases via beige cell induction.

Enhanced pan-peroxisome proliferator-activated receptor gene and protein expression in adipose tissue of diet-induced obese mice treated with telmisartan.

Telmisartan has previously been used to target obesity, showing peroxisome proliferator-activated receptor (PPAR) ß/δ-related effects in white adipose tissue (WAT). We sought to evaluate whether telmisartan enhances gene and protein expression of all PPAR isoforms in WAT and brown adipose tissue (BAT), as well as their downstream effects upon insulin resistance, adipokine profile and adaptive thermogenesis. Male C57BL/6 mice were fed standard chow (SC; 10% lipids) or high-fat diet (HF; 50% lipids) for 10 weeks. Animals were then randomly allocated into the following four groups: SC, SC-T, HF and HF-T. Telmisartan [10 mg (kg diet)(-1)] was administered for 4 weeks in the diet. Animals in the HF group were overweight and exhibited hypertension, insulin resistance, decreased energy expenditure, a pro-inflammatory adipokine profile and abnormal fat pad mass distribution. Animals in the HF group showed decreased expression of PPARα, ß/δ and γ in WAT and BAT, resulting in impaired glucose uptake and insufficient thermogenesis. Due to the improvement in the adipokine profile and enhanced insulin sensitivity with adequate insulin-stimulated glucose uptake after treatment with telmisartan, the activation of all PPAR isoforms in WAT was beneficial. In BAT, telmisartan induced sustained sympathetic activation, because the ß3-adrenergic receptor was induced by PPARß/δ, while uncoupling protein 1 was induced by PPARα to promote thermogenesis. Telmisartan exerted anti-obesity effects through higher pan-PPAR gene and protein expression. Upon PPARα, ß/δ and γ (pan-PPAR) agonism in adipose tissue of obese mice, telmisartan ameliorates inflammation and insulin resistance, as well as inducing non-shivering thermogenesis. Our results point to new therapeutic targets for the control of obesity and comorbidities through pan-PPAR-related effects.

Comparative effects of the renin-angiotensin system blockers on nonalcoholic fatty liver disease and insulin resistance in C57BL/6 mice.

BACKGROUND: The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. The current study evaluated the effects of RAS blockers in a model of diet-induced insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). METHODS: Male C57BL/6 mice were fed a standard chow (SC; 10% lipids, n=15) diet or a high-fat (HF; 50% lipids, n=60) diet for 8 weeks and then treated with aliskiren (HF-A; 50 mg/kg per day, n=15), enalapril (HF-E; 30 mg/kg per day, n=15), or losartan (HF-L; 10 mg/kg per day, n=15) for an additional 6 weeks. We assessed glucose and lipid metabolism, hepatic histopathology, the expression profile of genes and proteins affecting hepatic gluconeogenesis, RAS and insulin signaling, and lipid beta-oxidation and accumulation. The differences between the groups were tested via analysis of variance (ANOVA) and the post hoc Holm-Sidak test. RESULTS: All treatments restored the up-regulation of hepatic RAS. The enalapril treatment, but not aliskiren or losartan, was effective in improving leptin, glucose intolerance, IR, hepatic steatosis, and triglycerides and in preventing increased hepatic protein levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), and glucose transporter-2 (GLUT-2). Furthermore, enalapril improved the response to the deleterious effects of the HF diet by upregulating signal transduction through the insulin receptor substrate (IRS) 1/protein kinase B (Akt) pathway, as well as downregulating the protein levels and mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1c (SREBP-1c), and fatty acid synthase (FAS). CONCLUSIONS: Enalapril was the most successful treatment in protecting against hepatic IR and NAFLD by enhancing hepatic insulin action, leptin, and gluconeogenesis and by reducing the lipogenic pathway and lipid accumulation in the liver.