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Transcriptional control of energy metabolism: studies on FXR and PGC-1รก

2014-05-22Doctoral thesis Restricted access
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datacite.subject.fosCiรชncias Naturais::Ciรชncias Biolรณgicaspt_PT
dc.contributor.advisorRibeiro, Vera
dc.contributor.advisorRuas, Jorge L.
dc.contributor.authorCorreia, Jorge Miguel Pratas Camacho
dc.date.accessioned2016-03-03T10:04:51Z
dc.date.available2016-03-03T10:04:51Z
dc.date.issued2014-05-22
dc.date.submitted2014
dc.descriptionTese de doutoramento, Ciรชncias Biolรณgicas, Faculdade de Ciรชncias e Tenologia, Universidade do Algarve, 2014
dc.description.abstractSedentary lifestyles, combined with an environment of caloric abundance, have led to a remarkable increase in the incidence of obesity and diabetes. The resistance to insulin action observed in type 2 diabetes is a complex and multifactorial metabolic disorder. Several factors have been implicated in the development of insulin resistance, including systemic low-grade inflammation and ectopic lipid accumulation. The transcriptional regulators FXR and PGC-1ฮฑ have been shown to promote beneficial effects on energy metabolism, which can be explored to improve metabolic status in settings of insulin resistance. Here, we show that FXR regulates hepatic metabolism in an isoform-dependent manner. Expression of each human FXR variant in primary hepatocytes promoted robust and discrete changes in target gene expression. Importantly, expression of FXRฮฑ2 and FXRฮฑ4 decreased hepatocyte lipid accumulation and improved insulin sensitivity. Furthermore, FXRฮฑ2 expression increased fatty acid oxidation and ฮฒ-hydroxybutyrate production. In line with these observations, we observed that FXR splicing was dynamically regulated in mouse liver in response to fasting and physical exercise, with an increase in the relative expression of FXRฮฑ2. In addition, FXR expression is elevated in white adipose tissue of skeletal muscle-specific PGC-1ฮฑ1 transgenic mice (MCK-PGC-1ฮฑ1) and regulates adipocyte expression of major lipolytic mediators. Finally, we show that PGC-1ฮฑ1 promotes an anti-inflammatory biological response in skeletal muscle, repressing the classical NFฮบB pathway. MCK-PGC-1ฮฑ1 mice have decreased IKKฮฒ, p50 and p65 expression, which is accompanied by a strong increase in IฮบBฮฑ protein levels. Importantly, PGC-1ฮฑ1 enhances insulin-stimulated glycogen synthesis in cultured myotubes upon pro-inflammatory stimulation. Taken together, our results suggest that FXRฮฑ2 and PGC-1ฮฑ1 improve metabolic conditions implicated in the development of insulin resistance and therefore are attractive therapeutic targets for the treatment of obesityassociated metabolic disorders.pt_PT
dc.description.abstractO sedentarismo e o elevado consumo calรณrico tรชm conduzido a um aumento alarmante na incidรชncia de obesidade e diabetes. A resistรชncia ร  acรงรฃo da insulina, que ocorre em diabetes tipo 2, รฉ uma anomalia metabรณlica complexa e multifactorial. Vรกrios factores estรฃo associados ao desenvolvimento de resitรชncia ร  insulina, incluindo inflamaรงรฃo sistรฉmica e acumulaรงรฃo ectรณpica de lรญpidos. Os reguladores transcricionais FXR e PGC-1ฮฑ promovem efeitos benรฉficos ao nรญvel do metabolismo energรฉtico, que podem ser explorados para melhorar a condiรงรฃo metabรณlica em estados de resitรชncia ร  insulina. Nestes estudos, demonstramos que a regulaรงรฃo exercida pelo FXR ao nรญvel do metabolismo lipรญdico em hepatรณcitos depende da isoforma expressa. A expressรฃo de cada isoforma do FXR em hepatรณcitos primรกrios promove alteraรงรตes distintas na expressรฃo de genes alvo. A expressรฃo de FXRฮฑ2 ou FXRฮฑ4 diminui a acumulaรงรฃo lipรญdica em hepatรณcitos, o que resulta num aumento da sensibilidade ร  insulina. Ademais, a expressรฃo de FXRฮฑ2 promove a oxidaรงรฃo de รกcidos gordos e produรงรฃo de ฮฒ-hidroxibutirato. Em linha com estas observaรงรตes, o splicing do FXR รฉ alterado em situaรงรตes de jejum e exercรญcio fรญsico, com um aumento da expressรฃo relativa de FXRฮฑ2. Tambรฉm observรกmos que a expressรฃo do FXR se encontra elevada no tecido adiposo de ratinhos com expressรฃo transgรฉnica de PGC-1ฮฑ1 especificamente no mรบsculo esquelรฉtico (MCK-PGC-1ฮฑ1), participando na regulaรงรฃo de importantes fatores lipolรญticos. Finalmente, PGC-1ฮฑ1 promove uma resposta anti-inflamatรณria em mรบsculo esquelรฉtico, caracterizada por um decrรฉscimo na expressรฃo de IKKฮฒ, p50 e p65 e por um aumento dos nรญveis proteicos de IฮบBฮฑ, o que sugere um decrรฉscimo significativo na atividade do sistema NFฮบB. Estas alteraรงรตes resultam num aumento de sensibilidade ร  insulina em miotubos submetidos a estรญmulos pro-inflamatรณrios. Estes resultados sugerem que FXRฮฑ2 e PGC-1ฮฑ1 promovem melhorias em condiรงรตes metabรณlicas associadas com o desenvolvimento de resistรชncia ร  insulina, sendo portanto alvos terapรชuticos interessantes para o tratamento de doenรงas metabรณlicas associadas ร  obesidade.pt_PT
dc.description.sponsorshipFundaรงรฃo Para a Ciรชncia e Tecnologia (FCT): SFRH/BD/44825/2008pt_PT
dc.identifier.tid101289600
dc.identifier.urihttp://hdl.handle.net/10400.1/7773
dc.language.isoengpt_PT
dc.subjectCiรชncias biolรณgicaspt_PT
dc.subjectDiabetespt_PT
dc.subjectInsulinapt_PT
dc.subjectResistรชnciapt_PT
dc.subjectEnergiapt_PT
dc.subjectMetabolismopt_PT
dc.subjectExercรญciospt_PT
dc.titleTranscriptional control of energy metabolism: studies on FXR and PGC-1รกpt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
rcaap.rightsrestrictedAccesspt_PT
rcaap.typedoctoralThesispt_PT
thesis.degree.grantorUniversidade do Algarve. Faculdade de Ciรชncias e Tenologia
thesis.degree.levelDoutor
thesis.degree.nameDoutoramento em Ciรชncias Biolรณgicaspt_PT

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