No description available.

Vitamin A metabolites and retinoids may slow the progression of breast cancer and elicit anti-neoplastic properties similar to those of omega-3 fatty acids. Studies using animal models show a decrease in the incidence, growth and metastisis of mammary tumors in the presence of specific fatty acids. This effect is also seen with use of retinoids, specifically all-trans retinoic acid (AtRA). Thus, fatty acids may also alter retinoid homeostasis in mammary carcinoma cells (MCF-7s). The potential for inter/co dependency among fatty acids and retinoids is considerable, and here it has been hypothesized that a decrease in cancer progression will occur in the presence of both compounds. MCF-7’s were seeded in a 48 well plate at 5,000 cells per well. After 24 hr, cells were treated with either 1 µM AtRA alone, fatty acids alone, or AtRA + fatty acids. Fatty acid treatments (Linoleic, and Linolenic) were administered at 2.5 uM concentrations. Each fatty acid treatment was also combined with 1 µM AtRA to determine if there is a synergistic effect on slowing cell growth. Both culture media and treatments were changed at 24 hour intervals over a 3 day trial. When compared to the controls, cells treated with 1 µM AtRA or 2.5 µM Linolenic acid both inhibited cell growth. Interestingly, when combined with Linolenic acid, AtRA treatment resulted in a significant (nearly 50%) additional growth inhibition when compared to treatment with AtRA alone. Our results suggest that AtRA and Linolenic acid have a inter/co dependency that significantly inhibits breast cancer cell growth in vitro by 73.4 % compared to control, and 49.7% compared to AtRA alone over 72 hours. We conclude that AtRA and linolenic acid have a combined effect in breast cancer cell proliferation in-vitro and their role in dietary prevention warrants further investigation.

Le récepteur LSR est un acteur important du métabolisme hépatique, puisqu'il joue un rôle dans la clairance des lipoprotéines à ApoB/ApoE riches en triglycérides durant la période postprandiale. Dans cette étude, nous avons montré qu'un traitement in vitro par DHA peut augmenter les niveaux de protéine et d'activité LSR dans les cellules d'hépatome de souris Hepa 1-6. En toute cohérence, un régime supplémenté en DHA a conduit à élever les niveaux de protéine LSR hépatique chez la souris. Mais aucune de ces deux études n'a montré de changement au niveau des ARNm. Ceci suggère que l'enrichissement en DHA influe positivement sur le microenvironnement de LSR et son ancrage à la surface de la cellule. Nous avons ensuite étudié le rôle du récepteur PPAR[alpha] dans la régulation du gène lsr. Une analyse in silico nous a permis d'identifier des éléments PPRE dans la région 5' régulatrice du gène humain et de ses homologues de souris et de rat. Des traitements pharmacologiques par des agoniste et antagoniste spécifiques de PPAR[alpha] ont montré que ce récepteur est impliqué dans la régulation transcriptionnelle de l'expression du LSR dans les cellules Hepa 1 6. Enfin, une analyse transcriptomique a révélé une diminution de l'expression de PPAR[alpha] et d'autres gènes impliqués dans le métabolisme lipidique hépatique chez la souris LSR+/- sous régime standard ou riche en graisses. En conclusion, toutes ces études indiquent que l'activité LSR hépatique est sous le contrôle de facteurs nutritionnels capables d'activer divers mécanismes de régulation, faisant du LSR une cible d'intérêt potentiel pour des stratégies nutritionnelles ou thérapeutiques destinées à prévenir ou traiter les dyslipidémies / Lipolysis stimulated lipoprotein receptor (LSR) plays an important role in the clearance of ApoB/ApoE containing triglyceride-rich lipoproteins during postprandial phase. In this study, we demonstrated that in vitro treatment of mouse hepatoma cells, Hepa 1-6, with docosahexaenoic acid (DHA) led to an increase in LSR protein levels as well as its activity. Furthermore, the mice placed on the diet supplemented with DHA showed an increase in hepatic LSR protein. However, the mRNA levels remained unchanged in both in vitro and in vivo studies, suggesting that DHA enrichment may result in changes in LSR microenvironment that could affect its anchorage at the surface of cell membrane. Specific peroxisome proliferator response elements were identified in the upstream region of human, mouse and rat lsr gene by in silico analysis. We therefore sought to determine the role of the transcription factor, peroxisome proliferator-activated receptor (PPAR[alpha]), in LSR regulation. In vitro pharmacological studies using PPAR[alpha]-selective agonist and antagonist agents demonstrated that PPAR[alpha] is indeed involved in the transcriptional regulation of LSR expression. Furthermore, qPCR array analysis revealed the downregulation of PPAR[alpha] and various genes involved in hepatic lipid metabolism in LSR+/- mice on standard and high-fat diets. In conclusion, these studies show that the hepatic LSR activity is controlled by dietary factors that can activate various pathways involved in regulating lipid homeostasis, therefore representing LSR as a potential target for either nutritional or therapeutic strategies towards the prevention or treatment of dyslipidemia

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O objetivo do presente estudo foi avaliar se o Bezafibrato, um agonista PAN-PPAR, é capaz de aliviar a doença não alcoólica do fígado gorduroso (NAFLD) na prole de machos de mães C57BL/6 obesas. Fêmeas virgens foram alimentadas com uma dieta HL (hiperlipídica, 49% de lipídios) ou uma dieta C (controle, 10% de lipídios) por oito semanas antes do acasalamento e durante os períodos de gestação e lactação. A prole de machos foi subdividida em quatro grupos: C (dieta controle para as mães e filhotes); C/BZ (dieta controle para as mães e filhotes com tratamento com Bezafibrato[100mg/Kg]); HL (dieta HL para as mães e dieta controle para os filhotes); e HL/BZ (dieta HL para as mães e dieta controle para os filhotes com tratamento com Bezafibrato [100mg/Kg]). O tratamento com Bezafibrato começou na 12 semana e se manteve por três semanas. Análise do metabolismo, bioquímica, estereológica e por western-blotting foram realizadas. A dieta HL causou um fenótipo de sobrepeso nas mães e acarretou em uma intolerância oral à glicose com aumento da glicemia de jejum. A prole HL apresentou hiperfagia, ganho de massa corporal, altos níveis de triglicerídeo hepático e plasmático, esteatose hepática e aumento da expressão de proteínas lipogênicas concomitante com diminuição do receptor ativador de proliferação peroxissomal alfa (PPARα), que é responsável pela β-oxidação e aumento do receptor ativador de proliferação peroxissomal gama (PPARγ) e do elemento regulador de esterol ligante da proteína 1 (SREBP-1c) proteínas envolvidas na lipogênese hepática. Por outro lado, o tratamento com o Bezafibrato reverteu o quadro da programação metabólica no fígado, com uma melhora dos parâmetros morfológicos, bioquímicos e moleculares do fígado dos animais, com um aumento da ativação de PPARα em associação a uma diminuição do PPARγ e não alterando a expressão de SREBP-1c. Em conclusão, nós demonstramos que o tratamento com Bezafibrato melhora a NAFLD causada pela obesidade materna. / The aim of the present study was to evaluate whether Bezafibrate , a PAN-PPAR agonist, could attenuate non-alcoholic fatty liver disease (NAFLD) of male offspring from obese C57BL/6 dams. Dams were fed on a HF (high-fat, 49% lipids) diet or SC (standard chow; 10% lipids) diet for 8 weeks before mating and during gestation and lactation periods. Male offspring were subdivided into 4 groups: SC (standard-chow for dams and offspring); SC/BZ [standard-chow for dams and offspring with treatment with BZ (100mg/Kg)]; HF (high-fat diet for dams and standard-chow for offspring); HF/BZ [high-fat diet for dams and standard-show for offspring with treatment with Bezafibrate (100mg/Kg)]. Treatment with Bezafibrate started at 12th week and was maintained for 3 weeks. Metabolic measurements, biochemical analysis, stereological tools and western-blotting were performed. The HF diet yielded an overweight phenotype and an increase in oral glucose tolerance and fasting glucose of dams. The HF offspring presented hyperphagia, body mass gain, high levels of plasmatic and hepatic triglycerides, impairment of glucose metabolism, hepatic steatosis and high expression of lipogenic proteins concomitant to decreased expression of PPARα, which is responsible for β-oxidation. On the other hand, treatment with Bezafibrate reverted hepatic outcomes of metabolic programming, with an improvement of morphological, biochemical and molecular parameters of animals livers, with an increase of PPARα activation in association with a decrease of PPARγ expression and no changes in SREBP-1c expression. In conclusion, we demonstrated that treatment with Bezafibrate improved NAFLD caused by maternal obesity.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O objetivo do presente estudo foi avaliar se o Bezafibrato, um agonista PAN-PPAR, é capaz de aliviar a doença não alcoólica do fígado gorduroso (NAFLD) na prole de machos de mães C57BL/6 obesas. Fêmeas virgens foram alimentadas com uma dieta HL (hiperlipídica, 49% de lipídios) ou uma dieta C (controle, 10% de lipídios) por oito semanas antes do acasalamento e durante os períodos de gestação e lactação. A prole de machos foi subdividida em quatro grupos: C (dieta controle para as mães e filhotes); C/BZ (dieta controle para as mães e filhotes com tratamento com Bezafibrato[100mg/Kg]); HL (dieta HL para as mães e dieta controle para os filhotes); e HL/BZ (dieta HL para as mães e dieta controle para os filhotes com tratamento com Bezafibrato [100mg/Kg]). O tratamento com Bezafibrato começou na 12 semana e se manteve por três semanas. Análise do metabolismo, bioquímica, estereológica e por western-blotting foram realizadas. A dieta HL causou um fenótipo de sobrepeso nas mães e acarretou em uma intolerância oral à glicose com aumento da glicemia de jejum. A prole HL apresentou hiperfagia, ganho de massa corporal, altos níveis de triglicerídeo hepático e plasmático, esteatose hepática e aumento da expressão de proteínas lipogênicas concomitante com diminuição do receptor ativador de proliferação peroxissomal alfa (PPARα), que é responsável pela β-oxidação e aumento do receptor ativador de proliferação peroxissomal gama (PPARγ) e do elemento regulador de esterol ligante da proteína 1 (SREBP-1c) proteínas envolvidas na lipogênese hepática. Por outro lado, o tratamento com o Bezafibrato reverteu o quadro da programação metabólica no fígado, com uma melhora dos parâmetros morfológicos, bioquímicos e moleculares do fígado dos animais, com um aumento da ativação de PPARα em associação a uma diminuição do PPARγ e não alterando a expressão de SREBP-1c. Em conclusão, nós demonstramos que o tratamento com Bezafibrato melhora a NAFLD causada pela obesidade materna. / The aim of the present study was to evaluate whether Bezafibrate , a PAN-PPAR agonist, could attenuate non-alcoholic fatty liver disease (NAFLD) of male offspring from obese C57BL/6 dams. Dams were fed on a HF (high-fat, 49% lipids) diet or SC (standard chow; 10% lipids) diet for 8 weeks before mating and during gestation and lactation periods. Male offspring were subdivided into 4 groups: SC (standard-chow for dams and offspring); SC/BZ [standard-chow for dams and offspring with treatment with BZ (100mg/Kg)]; HF (high-fat diet for dams and standard-chow for offspring); HF/BZ [high-fat diet for dams and standard-show for offspring with treatment with Bezafibrate (100mg/Kg)]. Treatment with Bezafibrate started at 12th week and was maintained for 3 weeks. Metabolic measurements, biochemical analysis, stereological tools and western-blotting were performed. The HF diet yielded an overweight phenotype and an increase in oral glucose tolerance and fasting glucose of dams. The HF offspring presented hyperphagia, body mass gain, high levels of plasmatic and hepatic triglycerides, impairment of glucose metabolism, hepatic steatosis and high expression of lipogenic proteins concomitant to decreased expression of PPARα, which is responsible for β-oxidation. On the other hand, treatment with Bezafibrate reverted hepatic outcomes of metabolic programming, with an improvement of morphological, biochemical and molecular parameters of animals livers, with an increase of PPARα activation in association with a decrease of PPARγ expression and no changes in SREBP-1c expression. In conclusion, we demonstrated that treatment with Bezafibrate improved NAFLD caused by maternal obesity.

Evidências disponíveis na literatura sugerem uma conexão entre ingestão de frutose, síndrome metabólica e declínio cognitivo. Na sociedade ocidental, o aumento de casos de síndrome metabólica ocorreu em paralelo ao aumento do consumo de excesso de frutose na dieta. Além disso, animais que consomem excesso de frutose em sua dieta apresentam alterações típicas de resistência à insulina em seus cérebros, além de desenvolverem declínio cognitivo. Sabe-se que exercício físico é capaz de prevenir atrofia do hipocampo e atenuar declínio cognitivo. O objetivo desse estudo foi avaliar se exercício aeróbico é capaz de prevenir o declínio cognitivo associado a um excesso de frutose na dieta e investigar os mecanismos pelos quais isso poderia ocorrer. Ratos Wistar machos foram divididos em quatro grupos: controle sedentário, exercício, frutose sedentário e frutose+exercício. A memória operacional foi testada através do labirinto de Barnes. A sinalização de insulina e de moléculas relacionadas ao exercício foram avaliados no hipocampo e no músculo quadríceps através de Western Blot e PCR em tempo real. A ingestão de excesso de frutose induziu declínio cognitivo que não foi atenuado pelo exercício. O hipocampo dos animais que ingeriram frutose não apresentou deficiência na sinalização de insulina, mas apresentou leve diminuição em BDNF e sinaptofisina, o que foi acompanhado de diminuição significativa da expressão de PGC1alfa tanto no músculo quanto no hipocampo. O musculo quadríceps dos animais alimentados com frutose também mostrou uma diminuição significativa na expressão da miocina irisina (FNDC5) e de genes ligados à autofagia, ao transporte de glicose (GLUT4) e à oxidação de ácidos graxos (NR4A3, PPAR?, Erralfa). Treino aeróbico foi incapaz de reverter todas essas alterações. Em contraste, tratamento metformina foi capaz de prevenir o declínio cognitivo de animais que ingeriram excesso de frutose. Podemos concluir que ingestão de frutose prejudicou a expressão de genes críticos à adaptação do músculo ao exercício e, como resultado, atenuou efeitos benéficos do exercício no cérebro. Tratamento com metformina preveniu a queda na expressão de FNDC5 e BDNF e, consequentemente, o declínio cognitivo em ratos alimentados com frutose através de uma ação direta no cérebro, apesar de não prevenir os efeitos deletérios da frutose no músculo esquelético / Available evidence in the literature suggests a link between fructose ingestion, Metabolic Syndrome and cognitive impairment. In Western society, the rise in the frequency of Metabolic Syndrome was paralleled by a rise in consumption of a high fructose diet. Moreover, molecular alterations typically related to insulin resistance have been found in brains of fructose-induced insulin-resistant rats, and these rodents also develop cognitive deterioration. Physical exercise is well known to prevent hippocampal atrophy and to attenuate cognitive decline. The objective of this study was to evaluate if aerobic training can ameliorate cognitive decline associated with excessive fructose ingestion and to investigate the pathways through which this might occur. Male Wistar rats were divided into four groups: sedentary control, exercise, sedentary fructose, fructose+exercise. Working memory was assessed on the Barnes Maze. Intracellular insulin and exercise-related signaling molecules of the hippocampus and quadriceps femori were assayed using Western blot and Real time PCR. Fructose ingestion induced cognitive decline which was not attenuated by exercise. Insulin signaling was not impaired in the hippocampus in the fructose-fed animals, but there was a slight decrease in BDNF and synaptophysin in the hippocampus, accompanied by a significant decrease in exercise-induced expression of PGC1alpha both in the hippocampus and the muscle of exercised animals that ingested fructose. The quadriceps femori of fructose-fed animals also showed a significant decrease in expression of the myokine irisin (FNDC5) and of genes related to autophagy, glucose transport (GLUT4) and fatty acid oxidation (NR4A3, PPAR?, Err alpha). Exercise training was unable to reverse all of these alterations. Contrarily, metformin administration ameliorated cognitive decline in fructose-fed rats. We conclude that fructose feeding impaired expression of genes that are critical to skeletal muscle adaptation to exercise, which in turn attenuated the beneficial effects of exercise in the brain. Treatment with metformin was able to prevent the decline in expression of FNDC5 and BDNF ameliorating cognitive decline in fructose fed rats by direct action in the brain, despite being unable to reverse the effects of fructose feeding in the muscle

Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro / Este trabalho teve o objetivo de estudar o efeito de medicamentos com diferentes ações agonista PPAR (rosiglitazona, fenofibrato e bezafibrato) sobre o perfil lipídico, glicídico e alterações na massa corporal e morfologia do tecido adiposo e pancreático em modelo de diabetes e sobrepeso induzido por dieta. Camundongos C57BL/6 (2 meses de idade) foram alimentados com dieta padrão (SC, n=10) ou dieta hiperlipídica rica em sacarose (HFHS, n=40) por 6 semanas. Logo após, os animais HFHS foram subdividos em: HFHS não tratado e HFHS tratado com rosiglitazona (HFHS-Ro), fenofibrato (HFHS-Fe) ou bezafibrato (HFHS-Bz) (5 semanas). Os camundongos alimentados com dieta HFHS apresentaram maior glicemia e insulina de jejum (+33% e +138%, respectivamente), intolerância à glicose, resistência à insulina, aumento da massa corporal (MC) (+20%) e adiposidade, hipertrofia de adipócitos e redução da imunocoloração para adiponectina no tecido adiposo. No pâncreas houve aumento da massa (+28%), acúmulo de gordura (+700%), hipertrofia da ilhota (+38%) e redução da imunocoloração para GLUT-2 (-60%). A rosiglitazona diminuiu a glicemia e insulina de jejum, porém induziu o ganho de MC e hipertrofia cardíaca. O fenofibrato estabilizou a MC, enquanto o bezafibrato levou a perda de MC. Apenas o bezafibrato impediu a hipertrofia da ilhota. A imunocoloração para GLUT-2 foi aumentada por todos os medicamentos, e não houve alterações na imunocoloração para o PPARα. Sinais morfológicos de pancreatite foram vistos no grupo HFHS-Fe, apesar dos níveis normais de amilase e lipase séricos. A rosiglitazona exacerbou a infiltração intrapancreática de gordura (+75% vs. HFHS), e o bezafibrato aumento a imunocoloração para o PPARβ/δ nas ilhotas pancreáticas. Em conclusão, o bezafibrato apresentou um efeito mais amplo sobre as alterações metabólicas, morfológicas e biométricas decorrentes da dieta HFHS, sugerindo que a inibição das três isoformas do PPAR seria melhor do que a inibição de apenas uma isoforma. A rosiglitazona exacerbou o ganho de MC, a infiltração de gordura no pâncreas e induziu hipertrofia cardíaca, assim, é necessário cautela ao prescrever este medicamento a um paciente obeso. / This work aimed to evaluate the effect of peroxisome proliferator-activated receptor (PPAR) agonists (rosiglitazone, fenofibrate and bezafibrate) on lipid and glucose metabolism, body mass, and adipose and pancreatic tissue morphology in a model of diet-induced type 2 diabetes and overweight in mice. Two-month-old male C57BL/6 mice were fed a standard chow (SC, n=10) or a high-fat high-sucrose chow (HFHS, n=40) for 6 weeks, and then HFHS-fed mice were subdivided by treatment: untreated HFHS and HFHS treated with rosiglitazone (HFHS-Ro), fenofibrate (HFHS-Fe), or bezafibrate (HFHS-Bz) (5 weeks on medication). HFHS-fed mice have altered fasting glucose (+33%) and insulin (+138%), GI, IR, increased body mass (+20%) and fat pad weight, adipocyte hypertrophy, and decreased adiponectin immunostain. They also presented increased pancreatic (+28%) mass, intrapancreatic fat (+700%), islet hypertrophy (+38%), and decreased GLUT-2 immunostain (-60%). Rosiglitazone reduced fasting glucose and insulin but induced weight gain and heart hypertrophy. Fenofibrate impaired body mass gain, while bezafibrate induced weight loss. Only bezafibrate impaired islet hypertrophy. GLUT-2 immunostain was improved by all treatments, and there were no alterations in PPAR-α stain. There were morphological signs of pancreatitis in fenofibrate-treated mice, although there was no alteration in serum amylase and lipase. Rosiglitazone exacerbated pancreatic fat infiltration (+75% vs. HFHS group), and bezafibrate increased PPAR-β expression in pancreatic islets. In conclusion, bezafibrate showed a wider range of action on metabolic, morphologic, and biometric alterations due to HFHS intake, suggesting that inhibiting the three PPAR isoforms is better than inhibiting each isoform alone. Rosiglitazone exacerbated body mass gain, pancreatic fat infiltration and induced heart hypertrophy as well, thus, precaution has to be taken in prescribing rosiglitazone to obese patients.

Evidências disponíveis na literatura sugerem uma conexão entre ingestão de frutose, síndrome metabólica e declínio cognitivo. Na sociedade ocidental, o aumento de casos de síndrome metabólica ocorreu em paralelo ao aumento do consumo de excesso de frutose na dieta. Além disso, animais que consomem excesso de frutose em sua dieta apresentam alterações típicas de resistência à insulina em seus cérebros, além de desenvolverem declínio cognitivo. Sabe-se que exercício físico é capaz de prevenir atrofia do hipocampo e atenuar declínio cognitivo. O objetivo desse estudo foi avaliar se exercício aeróbico é capaz de prevenir o declínio cognitivo associado a um excesso de frutose na dieta e investigar os mecanismos pelos quais isso poderia ocorrer. Ratos Wistar machos foram divididos em quatro grupos: controle sedentário, exercício, frutose sedentário e frutose+exercício. A memória operacional foi testada através do labirinto de Barnes. A sinalização de insulina e de moléculas relacionadas ao exercício foram avaliados no hipocampo e no músculo quadríceps através de Western Blot e PCR em tempo real. A ingestão de excesso de frutose induziu declínio cognitivo que não foi atenuado pelo exercício. O hipocampo dos animais que ingeriram frutose não apresentou deficiência na sinalização de insulina, mas apresentou leve diminuição em BDNF e sinaptofisina, o que foi acompanhado de diminuição significativa da expressão de PGC1alfa tanto no músculo quanto no hipocampo. O musculo quadríceps dos animais alimentados com frutose também mostrou uma diminuição significativa na expressão da miocina irisina (FNDC5) e de genes ligados à autofagia, ao transporte de glicose (GLUT4) e à oxidação de ácidos graxos (NR4A3, PPAR?, Erralfa). Treino aeróbico foi incapaz de reverter todas essas alterações. Em contraste, tratamento metformina foi capaz de prevenir o declínio cognitivo de animais que ingeriram excesso de frutose. Podemos concluir que ingestão de frutose prejudicou a expressão de genes críticos à adaptação do músculo ao exercício e, como resultado, atenuou efeitos benéficos do exercício no cérebro. Tratamento com metformina preveniu a queda na expressão de FNDC5 e BDNF e, consequentemente, o declínio cognitivo em ratos alimentados com frutose através de uma ação direta no cérebro, apesar de não prevenir os efeitos deletérios da frutose no músculo esquelético / Available evidence in the literature suggests a link between fructose ingestion, Metabolic Syndrome and cognitive impairment. In Western society, the rise in the frequency of Metabolic Syndrome was paralleled by a rise in consumption of a high fructose diet. Moreover, molecular alterations typically related to insulin resistance have been found in brains of fructose-induced insulin-resistant rats, and these rodents also develop cognitive deterioration. Physical exercise is well known to prevent hippocampal atrophy and to attenuate cognitive decline. The objective of this study was to evaluate if aerobic training can ameliorate cognitive decline associated with excessive fructose ingestion and to investigate the pathways through which this might occur. Male Wistar rats were divided into four groups: sedentary control, exercise, sedentary fructose, fructose+exercise. Working memory was assessed on the Barnes Maze. Intracellular insulin and exercise-related signaling molecules of the hippocampus and quadriceps femori were assayed using Western blot and Real time PCR. Fructose ingestion induced cognitive decline which was not attenuated by exercise. Insulin signaling was not impaired in the hippocampus in the fructose-fed animals, but there was a slight decrease in BDNF and synaptophysin in the hippocampus, accompanied by a significant decrease in exercise-induced expression of PGC1alpha both in the hippocampus and the muscle of exercised animals that ingested fructose. The quadriceps femori of fructose-fed animals also showed a significant decrease in expression of the myokine irisin (FNDC5) and of genes related to autophagy, glucose transport (GLUT4) and fatty acid oxidation (NR4A3, PPAR?, Err alpha). Exercise training was unable to reverse all of these alterations. Contrarily, metformin administration ameliorated cognitive decline in fructose-fed rats. We conclude that fructose feeding impaired expression of genes that are critical to skeletal muscle adaptation to exercise, which in turn attenuated the beneficial effects of exercise in the brain. Treatment with metformin was able to prevent the decline in expression of FNDC5 and BDNF ameliorating cognitive decline in fructose fed rats by direct action in the brain, despite being unable to reverse the effects of fructose feeding in the muscle

Une croissance intra-utérine insuffisante représente, avec la prématurité et les malfor-mations congénitales, une des principales causes de morbidité et de mortalité néonatales. Ces pathologies sont liées entre elles, les nouveau-nés prématurés étant souvent atteints de RCIU (RCIU). Les études épidémiologiques récentes ont montré que le RCIU était associé à une augmentation de la morbidité respiratoire dès la période néonatale, avec, en particulier, une augmentation du risque de dysplasie broncho-pulmonaire (DBP), principale séquelle respira-toire de la prématurité. La DBP est caractérisée par des anomalies du développement alvéo-laire et vasculaire, considérées comme les conséquences d'agressions multiples sur un poumon immature. La physiopathologie exacte reste encore largement méconnue. Nous nous sommes intéressés dans ce travail au lien entre RCIU et DBP avec un abord expérimental et clinique. Alors que les études épidémiologiques sont relativement concordantes sur le lien entre RCIU et DBP, les études expérimentales, montrent des résultats divers tant sur le développement pulmonaire qu'au niveau moléculaire. Nous avons donc voulu identifier, dans un premier temps, un modèle de RCIU reproduisant les anomalies du développement alvéolaire observées chez l'Homme en utilisant trois modèles précédemment validés chez le rat : un modèle de res-triction protidique per-gestationnelle , un modèle de ligature unilatérale de l'artère utérine, un modèle d'injection d'un inhibiteur chimique de la NO synthase, le L NAME. Seule la restric-tion protidique anténatale permet de reproduire à long terme des lésions de l'alvéolisation proches de celles observées dans la DBP. En revanche, dans ce modèle, les modifications des principaux gènes identifiés précédemment dans les anomalies le développement alvéolaire ne sont pas observées, que ce soit avant, pendant ou après l'alvéolisation. Ce résultat nous a ame-né à entreprendre une étude multigénique qui a permis d'identifier plusieurs voies modifiées pendant l'alvéolisation dans ce modèle. Parmi celles-ci, les gènes impliqués dans la contractili-té et l'adhésion cellulaire, l'immunité ou la voie des " Peroxisome Proliferator-Activated Re-ceptor ". Dans la partie clinique de cette étude, nous avons évalué le risque de DBP chez les extrêmes prématurés atteints de RCIU dont les mères présentaient des signes de pathologie vasculaire de la grossesse (prééclampsie). Cette étude rétrospective unicentrique sur 184 en-fants a permis de comparer des enfants atteints de RCIU à des enfants eutrophes pris en charge de manière homogène. Le RCIU d'origine vasculaire multiplie le risque de DBP par 6. Un marqueur précoce de l'évolution vers une DBP est un taux de plaquettes bas à la naissance, évoquant le rôle d'un taux élevé de facteurs anti-angiogéniques circulants. Une étude est en cours pour corréler les facteurs anti-angiogéniques circulants présents chez les mères pré-éclamptiques au devenir respiratoire, en particulier à l'évolution vers une DBP, de leurs nou-veau-nés d'âge gestationnel inférieur à 30 semaines d'aménorrhée. En conclusion, nous avons montré expérimentalement que seule la restriction protidique anténatale chez le rat reproduisait les troubles de l'alvéolisation comparables à ceux observés dans la DBP. De nouvelles voies moléculaires potentiellement impliquées dans les anomalies de l'alvéolisation ont été mises en évidence. Par ailleurs, le rôle de facteurs anti-angiogéniques d'origine maternelle comme fac-teurs de développement d'une DBP est en cours d'évaluation.

Major depression is a highly prevalent mood disorder with chronic debilitating effects. Additional to a rising rate in incidence, depression is highly co–morbid with other psychiatric disorders, but also chronic cardiometabolic illnesses that present with an inflammatory component. The exact aetiology of depression is still unknown, being multifactorial in its possible aetiology. Various hypotheses have attempted to shed light on both endogenous and exogenous risk factors as well as the underlying pathology that may lead to the development of the disease. This has led to a wide range of mediators being implicated, including biogenic amines, the HPA–axis, neurotrophic factors, inflammatory agents, the cholinergic system and circadian rhythm, to name a few. The mechanisms of action of current treatment strategies, except for a few atypical and novel treatment approaches, are limited to interactions with monoamines and are at best only 65% effective. Many of these are also plagued by troubling side–effects, relapse and recurrence. It has therefore become imperative to explore novel targets for the treatment of depression that may produce more rapid, robust and lasting antidepressant effects with a less daunting side–effect profile. The strong co–morbidity between depression and various cardiometabolic disorders, including cardiovascular disease, atherosclerosis, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) has led to the proposal that a metabolic disturbance may be a vital component that drives inflammatory and immunological dysfunction in depression. Supporting of this is evidence for a role of inflammatory cytokines and neurotrophic factors in the pathogenesis of depression. It has also been demonstrated that a link exists between insulin– and nitric oxide (NO)– mediated pathways in the brain, which further highlights the role of oxidative stress and cell damage. Furthermore, evidence supports a role for oxidative stress and NO in T2DM and/or insulin resistance. Insulin has also been implicated in various physiological processes in the central nervous system (CNS) and may also influence the release and reuptake of neurotransmitters. Preclinical and clinical evidence has provided support for the antidepressant–like effects of insulin–sensitizing peroxisome proliferator activated receptor (PPAR)– agonists, such as rosiglitazone and pioglitazone. In preclinical studies, however, these effects are limited to acute treatment with pioglitazone or sub–chronic (5 days) treatment with rosiglitazone. It is well–recognized that such findings need to be confirmed by chronic treatment paradigms. The aim of the current study was therefore to further investigate the proposed antidepressant–like effects of pioglitazone in a genetic animal model of depression, the Flinders sensitive line (FSL) rat, using a chronic treatment protocol. The FSL rat model was reaffirmed as presenting with inherent depressive–like behaviour compared to its more resilient counterpart, the Flinders resistant line (FRL) rat. Moreover, imipramine demonstrated a robust and reliable antidepressant–like effect in these animals using the forced swim test (FST), thus confirming the face and predictive validity of the FSL rat model for depression. In contrast to previous preclinical studies, acute dose–ranging studies with pioglitazone in Sprague Dawley rats delivered no significant anti–immobility effects in the FST, whereas results similar to that seen in the dose–ranging studies were observed following chronic treatment using FSL rats. Since altered pharmacokinetics could possibly influence the drug’s performance, another route of administration, viz. the subcutaneous route, was utilized as an additional measure to exclude this possibility. The results of the subcutaneous study, however, were congruent with that observed after oral treatment. In order to confirm an association between altered insulin sensitivity and antidepressant action and demonstration by recent studies that thiazolidinediones may augment the efficacy of existing antidepressants, we therefore investigated whether concomitant treatment with gliclazide (an insulin releaser and insulin desensitizer) or pioglitazone (an insulin sensitizer) may alter the antidepressant–like effects evoked by chronic treatment with imipramine. Pioglitazone did not positively or negatively affect the antidepressant effect of imipramine, although gliclazide tended to decrease the anti–immobility effects induced by this antidepressant. Taken together and considering the current available literature, this finding supports evidence linking the insulin–PPAR pathway to depression. However, further explorative studies are required to delineate the role of insulin sensitivity and glucose homeostasis in depression and antidepressant response. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.