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Nutritional regulation of central fat mass and obesity-associated (FTO) expression, and its association with the central melanocortin signaling in the regulation of energy homeostasis

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dc.contributor.supervisor Mizuno, Tooru (Physiology) en
dc.contributor.author Poritsanos, Nicole Joanna
dc.date.accessioned 2010-11-22T18:07:20Z
dc.date.available 2010-11-22T18:07:20Z
dc.date.issued 2010-11-22T18:07:20Z
dc.identifier.citation Poritsanos, NJ (2010). Relationship between blood glucose levels and hepatic Fto mRNA expression in mice. Biochem Biophys Res Commun. 400(4):713-7. Epub 2010 Sep 9. PubMed PMID: 20816934. en
dc.identifier.citation Poritsanos, NJ (2008). Regulation of hepatic PPARgamma2 and lipogenic gene expression by melanocortin. Biochem Biophys Res Commun. 376(2):384-8. Epub 2008 Sep 18. PubMed PMID: 18789887. en
dc.identifier.uri http://hdl.handle.net/1993/4294
dc.description.abstract The central nervous system (CNS) melanocortin signaling pathway plays a critical role in the regulation of metabolism. However, the regulatory effects of CNS melanocortin signaling on hepatic lipid metabolism and fatty liver disease have not been well established. Although the activity of the CNS melanocortin system is regulated by metabolic signals, the mechanism for this regulation is not fully understood. Variants of the FTO (fat mass and obesity-associated) gene are associated with obesity and FTO is expressed in the hypothalamic neurons including proopiomelanocortin (POMC) neurons. Therefore, it is hypothesized that hypothalamic FTO plays a role in the regulation of metabolism by mediating the effect of metabolic signals on hypothalamic melanocortinergic neurons, and that impairments in this regulation may cause metabolic impairments including obesity and fatty liver disease. Intracerebroventricular (i.c.v.) treatment with SHU9119, a melanocortin antagonist, increased hepatic lipid accumulation and the expression of genes encoding lipogenic enzymes in lean mice. Conversely, i.c.v. treatment with MTII, a melanocortin agonist, reduced the expression of hepatic lipogenic genes in association with reduction in body weight in ob/ob mice, a mouse model of fatty liver disease. Immunohistochemical analysis demonstrated that Fto is co-expressed in both POMC and agouti-related protein (AgRP) neurons in the mouse hypothalamus. Fto mRNA and protein expression was reduced by fasting and increased by glucose treatment in nutritionally important hypothalamic nuclei. Fasting-induced reduction in hypothalamic Fto expression was observed in both lean wild-type and obese ob/ob mice, while the stimulatory effect of glucose on hypothalamic Fto expression was absent in ob/ob mice. These findings support the hypothesis that central melanocortin signaling regulates hepatic lipid metabolism in part by regulating de novo lipogenesis. Impairments in the central melanocortin signaling lead to the development of hepatic steatosis, while enhanced melanocortin signaling may be beneficial in reversing abnormal hepatic lipid metabolism in fatty liver disease (Poritsanos et al., 2008). These findings also support the hypothesis that Fto is expressed in the hypothalamic melanocortinergic neurons and is regulated by metabolic signals involving changes in CNS glucose availability and/or glucose action. Impairments in this regulation may cause metabolic impairments including obesity and fatty liver disease. en
dc.format.extent 7753523 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.rights info:eu-repo/semantics/openAccess
dc.subject Intracerebroventricular en
dc.subject SHU9119 en
dc.subject MTII en
dc.subject ob/ob mice en
dc.subject Fto en
dc.subject glucose sensing en
dc.subject melanocortin signaling en
dc.subject AgRP en
dc.subject POMC en
dc.subject de novo lipogenesis en
dc.subject fatty liver en
dc.subject fasting en
dc.subject Hepatic steatosis en
dc.subject Energy homeostasis en
dc.subject Metabolism en
dc.subject Leptin en
dc.subject Insulin en
dc.subject intraperitoneal en
dc.title Nutritional regulation of central fat mass and obesity-associated (FTO) expression, and its association with the central melanocortin signaling in the regulation of energy homeostasis en
dc.type info:eu-repo/semantics/doctoralThesis
dc.type doctoral thesis en_US
dc.degree.discipline Physiology en
dc.contributor.examiningcommittee Dodd, Janice (Physiology) Nyomba, Gregoire (Physiology) Fry, Mark (Biological Sciences) Belsham, Denise (Physiology, University of Toronto) en
dc.degree.level Doctor of Philosophy (Ph.D.) en
dc.description.note February 2011 en


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