Navegando por Autor "Festuccia, William Tadeu Lara"
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Item Dieta hiperlipídica materna desregula o metabolismo hepático da prole adulta F2.(2019) Sousa, Graziele Galdino de; Alzamora, Andréia Carvalho; Cota, Renata Guerra de Sá; Alzamora, Andréia Carvalho; Cota, Renata Guerra de Sá; Babá, Élio Hideo; Silva, Marcelo Eustáquio; Vieira, Paula Melo de Abreu; Festuccia, William Tadeu LaraO estado nutricional no início da vida está envolvido no fenótipo metabólico da prole. Dados anteriores de nosso laboratório demonstraram que o consumo de dieta hiperlipídica durante acasalamento, gestação e lactação (59 dias) induziu distúrbios característicos da síndrome metabólica em progenitoras da geração zero (G0), que foram transmitidos aos seus descendentes da primeira (F1) e segunda geração (F2), apesar de terem sido alimentados com dieta controle por 13 semanas pós-desmame. No entanto, os mecanismos que levam à desregulação metabólica na prole ainda não estão claros. Dessa forma, o presente estudo avaliou o efeito do consumo materno de dieta hiperlipídica na expressão de genes envolvidos no metabolismo hepático de glicose, lipídeos e colesterol da G0 e F2, a fim de determinar se os distúrbios metabólicos da F2 foram desencadeados pela desregulação de vias metabólicas hepáticas da G0, que persistiu até a F2. Para isso, ratos foram acasalados com ratas, ambos da linhagem Fischer com 90 dias de idade, não consanguíneos, para geração da prole F1. Machos e fêmeas da prole F1 com 90 dias de idade, não consanguíneos, foram acasalados para geração da prole F2. As progenitoras foram alimentadas com dieta hiperlipídica (grupo G0-DH) ou controle (grupo G0-DC) durante o acasalamento, gestação e lactação (59 dias). As proles F1 e F2 receberam dieta controle após desmame até completar 90 dias de idade. A prole F2 foi dividida em dois grupos de acordo com alimentação 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 hiperlipídica materna induziu aumento da glicemia de jejum, dos níveis séricos de triglicérides e insulina, do HOMAIR, da massa relativa do fígado, do conteúdo de triglicérides hepático e da peroxidação lipídica nos grupos G0-DH e F2-DH. As progenitoras G0-DH apresentaram ainda esteatose microvesicular intensa, aumento do conteúdo de colesterol hepático e da atividade da SOD. Também foi observado que a prole F2-DH apresentou esteatose microvesicular discreta e aumento dos níveis séricos das enzimas ALT e AST e do colesterol total e da AUC do TTOG. A análise da expressão de genes envolvidos no metabolismo hepático de glicose revelou que a dieta hiperlipídica materna induziu redução dos níveis de mRNA de Insr, Irs1 e Akt2 e aumento dos níveis de mRNA de Fbp1 nos grupos G0-DH e F2-DH. Além disso, as progenitoras G0-DH apresentaram aumento da expressão gênica de Gp. Em relação ao metabolismo de lipídeos, foi observado que as progenitoras G0-DH apresentaram aumento dos níveis de mRNA de Srebp1c e níveis similares de mRNA de Hadh. No entanto, foi visto que a prole F2-DH apresentou níveis similares de mRNA de Srebp1c e aumento dos níveis de mRNA de Hadh. Em relação à expressão de genes envolvidos no metabolismo hepático de colesterol, foi observado que as progenitoras G0-DH apresentaram aumento da expressão de mRNA de Hmgcr e Ldlr. Em contrapartida, foi observado que a prole F2- DH apresentou redução dos níveis de mRNA de Hmgcr e níveis similares de mRNA de Ldlr. A análise da expressão gênica de sirtuínas mostrou que os grupos G0-DH e F2-DH apresentaram redução dos níveis de mRNA de Sirt1, Sirt2, Sirt3 e Sirt7. Além disso, a prole F2-DH apresentou redução dos níveis de mRNA de Sirt5 e Sirt6. Nossos achados sugerem que o consumo de dieta hiperlipídica durante o acasalamento, a gestação e a amamentação induziu desregulação no metabolismo hepático da G0, que levou a distúrbios metabólicos que persistiram até a F2, indicando que a dieta hiperlipídica materna atuou como um desregulador metabólico hepático transgeracional na F2. Nossos dados reforçam a importância da nutrição materna para a saúde da segunda geração de descendentes.Item Expression of glycerokinase in brown adipose tissue is stimulated by the sympathetic nervose system.(2003) Festuccia, William Tadeu Lara; Cota, Renata Guerra de Sá; Kawashita, Nair Honda; Garófalo, Maria Antonieta Rissato; Evangelista, Elísio Alberto; Rodrigues, Vanderlei; Kettelhut, Isis do Carmo; Migliorini, Renato HéliosExpression of glycerokinase in brown adipose tissue is stimulated by the sympathetic nervous system. Am J Physiol Regul Integr Comp Physiol 284: R1536–R1541, 2003; 10.1152/ajpregu.00764.2002.—The effect of cold exposure (4°C) or prolonged norepinephrine infusion on the activity and mRNA levels of glycerokinase (GyK) was investigated in rat interscapular brown adipose tissue (BAT). Cold exposure for 12 and 24 h induced increases of 30% and 100%, respectively, in the activity of BAT GyK, which was paralleled by twofold and fourfold increase in enzyme mRNA levels. BAT hemidenervation resulted in reductions of 50% and 30% in GyK activity and in mRNA levels, respectively, in denervated pads from rats kept at 25°C, and suppressed in these pads the cold-induced increases in both GyK activity and mRNA levels. The increase in GyK activity induced by cold exposure was not affected by phenoxybenzamine, but was markedly inhibited by previous administration of propranolol or actinomycin D. BAT GyK activity did not change significantly after 6 h of continuous subcutaneous infusion of norepinephrine (20 g/h), but increased twofold and fourfold after 12 and 24 h, with no further increase after 72 h of infusion. Norepinephrine infusion also activated mRNA production, but the effect was comparatively smaller than that on enzyme activity. -Adrenergic agonists also stimulated GyK activity with the following relative magnitude of response: CL316243 ( 3) isoproterenol (non-selective) dobutamine ( 1). In vitro rates of incorporation of glycerol into glyceride-glycerol were increased in BAT from rats exposed to cold. The data suggest that in conditions of a sustained increase in BAT sympathetic flow there is a stimulation of GyK gene expression at the pretranslational level, with increased enzyme activity, mediated by -adrenoreceptors, mainly 3.Item Liver lipidome signature and metabolic pathways in nonalcoholic fatty liver disease induced by a high-sugar diet.(2021) Oliveira, Daiane Teixeira de; Chaves Filho, Adriano de Britto; Yoshinaga, Marcos Yukio; Paiva, Nívia Carolina Nogueira de; Carneiro, Cláudia Martins; Miyamoto, Sayuri; Festuccia, William Tadeu Lara; Cota, Renata Guerra de SáDietary sugar is an important determinant of the development and progression of nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms underlying the deleterious effects of sugar intake on NAFLD under energy-balanced conditions are still poorly understood. Here, we provide a comprehensive analysis of the liver lipidome and mechanistic insights into the pathogenesis of NAFLD induced by the chronic consumption of high-sugar diet (HSD). Newly weaned male Wistar rats were fed either a standard chow diet or an isocaloric HSD for 18 weeks. Livers were harvested for histological, oxidative stress, gene expression, and lipidomic analyses. Intake of HSD increased oxidative stress and induced severe liver injury, microvesicular steatosis, and ballooning degeneration of hepatocytes. Using untargeted lipidomics, we identified and quantified 362 lipid species in the liver. Rats fed with HSD displayed increased hepatic levels of triacylglycerol enriched in saturated and monounsaturated fatty acids, lipids related to mitochondrial function/structure (phosphatidylglycerol, cardiolipin, and ubiquinone), and acylcarnitine (an intermediate lipid of fatty acid beta-oxidation). HSD-fed animals also presented increased levels of some species of membrane lipids and a decreased content of phospholipids containing omega-6 fatty acids. These changes in the lipidome were associated with the downregulation of genes involved in fatty acid oxidation in the liver. In conclusion, our data suggest that the chronic intake of a HSD, even under isocaloric conditions, induces lipid overload, and inefficient/impaired fatty acid oxidation in the liver. Such events lead to marked disturbance in hepatic lipid metabolism and the development of NAFLD.Item PPARγ is a major regulator of branched-chain amino acid blood levels and catabolism in white and brown adipose tissues.(2018) Blanchard, Pierre-Gilles; Moreira, Rafael Junges; Castro, Érique de; Caron, Alexandre; Côté, Marie; Andrade, Maynara Lucca; Silva, Tiago Eugênio Oliveira da; Silva, Milene Ortiz; Peixoto, Álbert Souza; Ruas, France Anne Dias; Gélinas, Yves; Cota, Renata Guerra de Sá; Deshaies, Yves; Festuccia, William Tadeu LaraObjective We investigated whether PPARγ modulates adipose tissue BCAA metabolism, and whether this mediates the attenuation of obesity-associated insulin resistance induced by pharmacological PPARγ activation. Methods Mice with adipocyte deletion of one or two PPARγ copies fed a chow diet and rats fed either chow, or high fat (HF) or HF supplemented with BCAA (HF/BCAA) diets treated with rosiglitazone (30 or 15 mg/kg/day, 14 days) were evaluated for glucose and BCAA homeostasis. Results Adipocyte deletion of one PPARγ copy increased mice serum BCAA and reduced inguinal white (iWAT) and brown (BAT) adipose tissue BCAA incorporation into triacylglycerol, as well as mRNA levels of branched-chain aminotransferase (BCAT)2 and branched-chain α-ketoacid dehydrogenase (BCKDH) complex subunits. Adipocyte deletion of two PPARγ copies induced lipodystrophy, severe glucose intolerance and markedly increased serum BCAA. Rosiglitazone abolished the increase in serum BCAA induced by adipocyte PPARγ deletion. In rats, HF increased serum BCAA, such levels being further increased by BCAA supplementation. Rosiglitazone, independently of diet, lowered serum BCAA and upregulated iWAT and BAT BCAT and BCKDH activities. This was associated with a reduction in mTORC1-dependent inhibitory serine phosphorylation of IRS1 in skeletal muscle and whole-body insulin resistance evaluated by HOMA-IR. Conclusions PPARγ, through the regulation of both BAT and iWAT BCAA catabolism in lipoeutrophic mice and muscle insulin responsiveness and proteolysis in lipodystrophic mice, is a major determinant of circulating BCAA levels. PPARγ agonism, therefore, may improve whole-body and muscle insulin sensitivity by reducing blood BCAA, alleviating mTORC1-mediated inhibitory IRS1 phosphorylation.Item Rosiglitazone-induced heart remodelling is associated with enhanced turnover of myofibrillar protein and mTOR activation.(2009) Festuccia, William Tadeu Lara; Laplante, Mathieu; Brûlé, Sophie; Houde, Vanessa P.; Achouba, Adel; Lachance, Dominic; Pedrosa, Maria Lúcia; Silva, Marcelo Eustáquio; Cota, Renata Guerra de Sá; Couet, Jacques; Arsenault, Marie; Marette, André; Deshaies, YvesWe investigated cardiac hypertrophy elicited by rosiglitazone treatment at the level of protein synthesis/ degradation, mTOR, MAPK and AMPK signalling pathways, cardiac function and aspects of carbohydrate/ lipid metabolism. Hearts of rats treated or not with rosiglitazone (15 mg/kg day) for 21 days were evaluated for gene expression, protein synthesis, proteasome and calpain activities, signalling pathways, and function by echocardiography. Rosiglitazone induced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectin, reduced heart rate and increased stroke volume. Rosiglitazone robustly increased heart glycogen content (∼400%), an effect associated with increases in glycogenin and UDPG-PPL mRNA levels and glucose uptake, and a reduction in glycogen phosphorylase expression and activity. Cardiac triglyceride content, lipoprotein lipase activity and mRNA levels of enzymes involved in fatty acid oxidation were also reduced by the agonist. Rosiglitazone-induced cardiac hypertrophy was associated with an increase in myofibrillar protein content and turnover (increased synthesis and an enhancement of calpain-mediated myofibrillar degradation). In contrast, 26S β5 chymotryptic proteasome activity and mRNA levels of 20S β2 and β5 and 19S RPN 2 proteasome subunits along with the ubiquitin ligases atrogin and CHIP were all reduced by rosiglitazone. These morphological and biochemical changes were associated with marked activation of the key growth-promoting mTOR signalling pathway, whose pharmacological inhibition with rapamycin completely blocked cardiac hypertrophy induced by rosiglitazone. The study demonstrates that both arms of protein balance are involved in rosiglitazone-induced cardiac hypertrophy, and establishes the mTOR pathway as a novel important mediator therein.