Oral Ang-(1-7) treatment improves white adipose tissue remodeling and hypertension in rats with metabolic syndrome.

Objective: Angiotensin (Ang)-(1-7) has preventive effects on metabolic syndrome (MetS). The aim of this study was to evaluate the therapeutic effect of oral Ang-(1-7) on mean arterial pressure (MAP), insulin resistance (IR), inflammatory process, and remodeling of white adipose tissue (WAT) in rats with establishedMetS. Methods: Rats were subjected to control (CT; AIN-93M) or high-fat (HF) diets for 13 wk to induce MetS and treated with Ang-(1-7) or vehicle (V) for the last 6 wk. At the end of 13 wk, MAP, biochemical and histological parameters, and uncoupling protein (UCP) and inflammatory gene expression were determined by quantitative reverse transcription polymerase chain reaction. Results: HF-V rats showed increased visceral fat deposition, inflammatory cytokine expression, hyperplasia, and hypertrophy in retroperitoneal (WAT) and brown adipose tissue (BAT). Additionally, the gastrocnemius muscle reduced UCP-3 and increased the UCP-1 expression in BAT. HF-V also elevated levels of plasma insulin, glucose, homeostatic model assessment (HOMA) of IR and HOMA-b, and increased body mass, adiposity, and MAP. Ang-(1-7) treatment in rats with MetS [HF-Ang-(1-7)] reduced WAT area, number of adipocytes, and expression of proinflammatory adipokines in WAT and BAT and increased UCP-3 in gastrocnemius muscle and UCP-1 expression in BAT compared with the HF-V group. These events prevented body mass gain, reduced adiposity, and normalized fasting plasma glucose, insulin levels, HOMA-IR, HOMA-b, and MAP. Conclusion: Data from the present study demonstrated that oral Ang-(1-7) treatment is effective in restoring biochemical parameters and hypertension in established MetS by improving hypertrophy and hyperplasia in WAT and inflammation in adipose tissue, and regulating metabolic processes in the gastrocnemius muscle and BAT

Dieta hiperlip?dica materna desregula o metabolismo hep?tico da prole adulta F2.

Programa de P?s-Gradua??o em Ci?ncias Biol?gicas. N?cleo de Pesquisas em Ci?ncias Biol?gicas, Pr?-Reitoria de Pesquisa de P?s Gradua??o, Universidade Federal de Ouro Preto.O estado nutricional no in?cio da vida est? envolvido no fen?tipo metab?lico da prole. Dados anteriores de nosso laborat?rio demonstraram que o consumo de dieta hiperlip?dica durante acasalamento, gesta??o e lacta??o (59 dias) induziu dist?rbios caracter?sticos da s?ndrome metab?lica em progenitoras da gera??o zero (G0), que foram transmitidos aos seus descendentes da primeira (F1) e segunda gera??o (F2), apesar de terem sido alimentados com dieta controle por 13 semanas p?s-desmame. No entanto, os mecanismos que levam ? desregula??o metab?lica na prole ainda n?o est?o claros. Dessa forma, o presente estudo avaliou o efeito do consumo materno de dieta hiperlip?dica na express?o de genes envolvidos no metabolismo hep?tico de glicose, lip?deos e colesterol da G0 e F2, a fim de determinar se os dist?rbios metab?licos da F2 foram desencadeados pela desregula??o de vias metab?licas hep?ticas da G0, que persistiu at? a F2. Para isso, ratos foram acasalados com ratas, ambos da linhagem Fischer com 90 dias de idade, n?o consangu?neos, para gera??o da prole F1. Machos e f?meas da prole F1 com 90 dias de idade, n?o consangu?neos, foram acasalados para gera??o da prole F2. As progenitoras foram alimentadas com dieta hiperlip?dica (grupo G0-DH) ou controle (grupo G0-DC) durante o acasalamento, gesta??o e lacta??o (59 dias). As proles F1 e F2 receberam dieta controle ap?s desmame at? completar 90 dias de idade. A prole F2 foi dividida em dois grupos de acordo com alimenta??o da G0: prole F2 de progenitoras G0-DC (grupo F2-DC) e prole F2 de progenitoras G0-DH (grupo F2-DH). Nossos resultados revelaram que a dieta hiperlip?dica materna induziu aumento da glicemia de jejum, dos n?veis s?ricos de triglic?rides e insulina, do HOMAIR, da massa relativa do f?gado, do conte?do de triglic?rides hep?tico e da peroxida??o lip?dica nos grupos G0-DH e F2-DH. As progenitoras G0-DH apresentaram ainda esteatose microvesicular intensa, aumento do conte?do de colesterol hep?tico e da atividade da SOD. Tamb?m foi observado que a prole F2-DH apresentou esteatose microvesicular discreta e aumento dos n?veis s?ricos das enzimas ALT e AST e do colesterol total e da AUC do TTOG. A an?lise da express?o de genes envolvidos no metabolismo hep?tico de glicose revelou que a dieta hiperlip?dica materna induziu redu??o dos n?veis de mRNA de Insr, Irs1 e Akt2 e aumento dos n?veis de mRNA de Fbp1 nos grupos G0-DH e F2-DH. Al?m disso, as progenitoras G0-DH apresentaram aumento da express?o g?nica de Gp. Em rela??o ao metabolismo de lip?deos, foi observado que as progenitoras G0-DH apresentaram aumento dos n?veis de mRNA de Srebp1c e n?veis similares de mRNA de Hadh. No entanto, foi visto que a prole F2-DH apresentou n?veis similares de mRNA de Srebp1c e aumento dos n?veis de mRNA de Hadh. Em rela??o ? express?o de genes envolvidos no metabolismo hep?tico de colesterol, foi observado que as progenitoras G0-DH apresentaram aumento da express?o de mRNA de Hmgcr e Ldlr. Em contrapartida, foi observado que a prole F2- DH apresentou redu??o dos n?veis de mRNA de Hmgcr e n?veis similares de mRNA de Ldlr. A an?lise da express?o g?nica de sirtu?nas mostrou que os grupos G0-DH e F2-DH apresentaram redu??o dos n?veis de mRNA de Sirt1, Sirt2, Sirt3 e Sirt7. Al?m disso, a prole F2-DH apresentou redu??o dos n?veis de mRNA de Sirt5 e Sirt6. Nossos achados sugerem que o consumo de dieta hiperlip?dica durante o acasalamento, a gesta??o e a amamenta??o induziu desregula??o no metabolismo hep?tico da G0, que levou a dist?rbios metab?licos que persistiram at? a F2, indicando que a dieta hiperlip?dica materna atuou como um desregulador metab?lico hep?tico transgeracional na F2. Nossos dados refor?am a import?ncia da nutri??o materna para a sa?de da segunda gera??o de descendentes.Early nutritional status is involved in the offspring metabolic phenotype. Previous data from our laboratory showed that consumption of hyperlipidic diet during mating, gestation and lactation (59 days) induced disorders characteristic of the metabolic syndrome in progenitors of zero generation (G0), which were transmitted to their descendants of the first (F1) and second generation (F2), although they were fed a control diet for 13 weeks after weaning. However, the mechanisms that lead to metabolic dysregulation in the offspring are still unclear. Thus, the present study evaluated the effect of maternal consumption of hyperlipidic diet on the expression of genes involved in the hepatic metabolism of glucose, lipids and cholesterol of G0 and F2, in order to determine if the metabolic disorders of F2 were triggered by deregulation of pathways hepatic metabolism of G0, which persisted up to F2. For this, rats were mated with rats, both of the Fischer lineage with 90 days of age, non-consanguineous, for F1 offspring generation. Males and females of F1 offspring, 90 days old, nonconsanguineous, were mated to F2 offspring generation. The progenitors were fed hyperlipid diet (G0-DH group) or control (G0-DC group) during mating, gestation and lactation (59 days). The F1 and F2 offspring received control diet after weaning until 90 days of age. F2 offspring were divided into two groups according to G0 feeding: F2 offspring of G0-DC progenitors (F2-DC group) and F2 offspring of G0-DH progenitors (F2-DH group). Our results revealed that the maternal hyperlipidic diet induced an increase in fasting glycemia, triglyceride and insulin serum levels, HOMA-IR, liver relative mass, liver triglyceride content and lipid peroxidation in G0-DH and F2-DH groups. G0-DH progenitors also showed intense microvesicular steatosis, increased hepatic cholesterol content and SOD activity. It was also observed that the F2-DH offspring showed discrete microvesicular steatosis and increased serum levels of ALT and AST and total cholesterol and AUC of the TTOG. Analysis of the expression of genes involved in glucose hepatic metabolism revealed that maternal hyperlipidic diet reduced Insr, Irs1 and Akt2 mRNA levels and increased Fbp1 mRNA levels in the G0- DH and F2-DH groups. Furthermore, the G0-DH progenitors showed increased Gp gene expression. Regarding lipid metabolism, it was observed that the G0-DH progenitors showed increased levels of Srebp1c mRNA and similar levels of Hadh mRNA. However, it was seen that F2-DH offspring showed similar levels of Srebp1c mRNA and increased levels of Hadh mRNA. Regarding the expression of genes involved in the hepatic metabolism of cholesterol, it was observed that the G0-DH progenitors showed increased mRNA expression of Hmgcr and Ldlr. In contrast, it was observed that the F2-DH offspring presented reduction in Hmgcr mRNA levels and similar levels of Ldlr mRNA. Analysis of the sirtuin gene expression showed that the G0-DH and F2-DH groups showed reduction of the mRNA levels of Sirt1, Sirt2, Sirt3 and Sirt7. Furthermore, the F2-DH offspring presented reduction of the mRNA levels of Sirt5 and Sirt6. Our findings suggest that consumption of hyperlipidic diet during mating, gestation, and lactation induced dysregulation in the hepatic metabolism of G0, which led to metabolic disorders that persisted up to F2, indicating that the maternal hyperlipidic diet acted as a transgenerational hepatic metabolic disregulator in F2. Our data reinforce the importance of maternal nutrition for the health of the second generation of descendants

Diferentes esp?cies reativas e neurotransmissores modulam os efeitos hipotensores da Ang II e Ang-(1-7) na CVLM em ratos com hipertens?o renovascular 2R1C.

Programa de P?s-Gradua??o em Ci?ncias Biol?gicas. N?cleo de Pesquisas em Ci?ncias Biol?gicas, Pr?-Reitoria de Pesquisa de P?s Gradua??o, Universidade Federal de Ouro Preto.A hipertens?o est? associada com uma disfun??o do sistema renina-angiotensina (SRA) e aumento do estresse oxidativo no bulbo ventrolateral caudal (CVLM). Estudos mostraram que a microinje??o de angiotensina (Ang) Ang II e Ang-(1-7) na CVLM induzem efeitos hipotensores similares em ratos normotensos SHAM e com hipertens?o renovascular 2R1C. Em adi??o, tem sido descrito que o ?nion super?xido (O2?-) participa dos efeitos da Ang II, enquanto que o ?xido n?trico (NO) modula as a??es da Ang-(1-7) em regi?es perif?ricas e centrais e que os neurotransmissores amino?cidos participam dos efeitos das angiotensinas em ?reas centrais. Assim, o objetivo do presente estudo foi avaliar se diferentes esp?cies reativas (ER) como O2?- e NO e neurotransmissores como glutamato e GABA estariam envolvidos nos efeitos hipotensores induzidos pelas microinje??es de Ang II e Ang-(1-7) na CVLM em ratos 2R1C. Ap?s 28 dias da cirurgia SHAM e 2R1C, ratos Fischer foram anestesiados (uretana, 1,2 g/kg, ip), posicionados em um aparelho estereot?xico para procedimento de microinje??o de drogas na CVLM e instrumentados para registro da press?o arterial m?dia (PAM) e frequ?ncia card?aca (FC). Ang II (40 pmol) ou Ang-(1-7) (40 pmol) foram microinjetadas na CVLM antes e 5, 15 e 30 minutos (min) ap?s a microinje??o de L-NAME (inibidor n?o espec?fico da ?xido n?trico s?ntase, NOS, 10 nmol) ou vitamina C (VIT C, antioxidante ?cido asc?rbico, 10 nmol) ou bicuculina (BIC, antagonista do receptor GABAA, 10 pmol) ou ?cido quinur?nico (KYN, antagonista dos receptores ionotr?picos do glutamato, 5 nmol) em ratos SHAM e 2R1C. A microinje??o de Ang II e Ang-(1-7) na CVLM induziu efeito hipotensor similar em ratos SHAM e 2R1C. A microinje??o de L-NAME na CVLM produziu queda similar na PAM e FC em ratos SHAM e 2R1C. Enquanto, a microinje??o de VIT C na CVLM produziu queda na PAM e FC somente em ratos 2R1C. A microinje??o de BIC na CVLM produziu queda na PAM e FC em ratos SHAM e 2R1C. No entanto, o efeito hipotensor induzido pela microinje??o de BIC na CVLM foi maior nos animais 2R1C comparado aos animais SHAM. J?, a microinje??o de KYN na CVLM produziu aumento na PAM e FC em ratos SHAM e 2R1C. Em adi??o, a microinje??o de L-NAME na CVLM aumentou o efeito hipotensor da Ang-(1-7) por at? 45 min em ratos SHAM e por apenas 5 min em ratos 2R1C e n?o alterou o efeito hipotensor da Ang II na CVLM em ratos SHAM e 2R1C. Ao contr?rio, a VIT C aboliu por at? 15 min o efeito hipotensor da Ang II na CVLM em ratos SHAM e 2R1C e n?o alterou o efeito hipotensor da Ang-(1-7) na CVLM em ambos os grupos. Al?m disso, a BIC diminui o efeito hipotensor da Ang-(1-7) por at? 30 min em ratos SHAM e por apenas 5 min em ratos 2R1C e n?o alterou o efeito hipotensor da Ang II na CVLM em ratos SHAM e 2R1C. J?, o KYN aumentou o efeito hipotensor da Ang II por at? 15 min em ratos SHAM e 2R1C e n?o alterou o efeito hipotensor da Ang-(1-7) na CVLM em ambos os grupos. Nossos dados em conjunto mostram a participa??o do O2 ?- e do GABA na CVLM na hipertens?o renovascular 2R1C. Al?m disso, os efeitos hipotensores similares induzidos pela Ang II e Ang-(1-7) na CVLM ocorrem atrav?s de mecanismos distintos, sendo que, o NO e o GABA participam predominantemente do efeito hipotensor da Ang-(1-7), enquanto o O2?- e o glutamato participam predominantemente do efeito hipotensor da Ang II na CVLM em ratos normotensos e hipertensos 2R1C. Esses dados mostram que diferentes vias e/ou mediadores intracelulares est?o envolvidos nos efeitos induzidos pela Ang II e Ang-(1-7) na CVLM.Hypertension is associated with a dysfunction of the renin-angiotensin system (RAS) and increased oxidative stress in the caudal ventrolateral medulla (CVLM). Studies showed that microinjection of angiotensin (Ang) Ang II and Ang-(1-7) in the CVLM induce hypotensive effects similar in SHAM normotensive and with 2K1C renovascular hypertension rats. In addition, it has been reported that superoxide anion (O2 ?-) participates in the effects of Ang II, whereas nitric oxide (NO) modulates the actions of Ang-(1-7) in peripheral and central regions and that the amino acid neurotransmitters participate in the effects of angiotensins in the central areas. Thereby, the objective of the present study was to evaluate whether different reactive species (RS) as O2?- and NO and neurotransmitters as glutamate and GABA were involved in the hypotensives effects induced by microinjections of Ang II and Ang-(1-7) in the CVLM in 2K1C rats. 28 days after surgery 2K1C and SHAM, Fischer rats were anesthetized (urethane, 1.2 g/kg, ip), positioned in a stereotaxic apparatus for procedure of drugs microinjection in CVLM and instrumented to record mean arterial pressure (MAP) and heart rate (HR). Ang II (40 pmol) or Ang-(1-7) (40 pmol) were microinjected in the CVLM before and 5, 15 and 30 minutes (min) after microinjection of L-NAME (non-specific inhibitor of nitric oxide synthase, NOS, 10 nmol) or vitamin C (VIT C, ascorbic acid antioxidant, 10 nmol) or bicuculline (BIC, GABAA receptor antagonist, 10 pmol) or kynurenic acid (KYN, ionotropic glutamatergic receptor antagonist, 5 nmol) in SHAM and 2K1C rats. CVLM microinjection of Ang II and Ang-(1-7) induced similar hypotensive effect in SHAM and 2K1C rats. CVLM microinjection of L-NAME produced similar fall in MAP and HR in SHAM and 2K1C rats, while CVLM microinjection of VIT C produced fall in MAP and HR only in 2K1C rats. CVLM microinjection of BIC produced fall in MAP and HR in SHAM and 2K1C rats. However, the hypotensive effect induced by microinjection of BIC in the CVLM was higher in 2K1C animals compared to SHAM animals. Already, the CVLM microinjection of KYN produced an increase in MAP and HR in SHAM and 2K1C rats. In addition, CVLM microinjection of L-NAME increased the hypotensive effect of Ang-(1-7) up to 45 min in SHAM rats and up to 5 min in 2K1C rats and did not alter the hypotensive effect induced by CVLM microinjection of Ang II in SHAM and 2K1C rats. In contrast, VIT C abolished up to 15 minutes the hypotensive effect of Ang II in the CVLM in 2K1C and SHAM rats and did not change the hypotensive effect of Ang-(1-7) in the CVLM in both groups. Furthermore, the BIC decreases the hypotensive effect of Ang-(1-7) up to 30 min in SHAM rats and up to 5 min in 2K1C rats and did not alter the hypotensive effect of Ang II in the CVLM in SHAM and 2K1C rats. Already, KYN increased hypotensive effect of Ang II up to 15 min in SHAM and 2K1C rats and did not change the hypotensive effect of Ang-(1-7) in the CVLM in both groups. Our data show the participation of the O2?- and GABA in the CVLM in 2K1C renovascular hypertension. Moreover, similar hypotensives effects induced by Ang II and Ang-(1-7) in the CVLM occur through distinct mechanisms, being that, NO and GABA predominantly participate hypotensive effect of Ang-(1 -7), while the O2?- and glutamate predominantly participate in the hypotensive effect of Ang II in the CVLM in normotensive and 2K1C hypertensive rats. These data show that different pathways and/or intracellular mediators are involved in the effects induced by Ang II and Ang-(1-7) in the CVLM

High-sugar diet intake, physical activity, and gut microbiota crosstalk: Implications for obesity in rats

This study aims to evaluate the effect of long-term high-sugar diet (HSD) intake and regular physical activity on gut microbiota as well as its health impact. Weaned male Wistar rats were fed with standard chow diet (SSD) or HSD ad libitum and subjected or not to regular swimming training with a workload (2% of body weight) for 15 weeks. Feces samples were used on microbiome analysis using 16S rRNA amplicon sequencing. HSD increased body mass, adipose cushions, and the serum levels of triglycerides and VLDL, also changed the bacteria taxons associated with metabolic disorders (increase taxons belonging to Proteobacteria phylum and decrease Pediococcus genus); the swim training reverted these changes. SSD intake increased the abundance of bacteria associated with metabolization of dietary fiber. Training in association with SSD consumption beneficially modulated the microbiota, increasing the Bacteroidetes, Bacteroidaceae, Porphyromonadaceae, Parabacteroides, and Lactobacillaceae, and decreasing the Firmicute/Bacteroidetes ratio; training was not able to maintain this profile in animals SHD-fed. Physical training modulates the gut microbiota reversing the obesogenic response caused by SHD. However, training itself is not efficient for up-regulating the probiotic bacteria in comparison to its association with a balanced diet