Type 2 Diabetes mellitus (T2D) as part of the cluster of clinical disorders that define Metabolic Syndrome is characterised by a major failure of the mechanisms controlling fuel homeostasis secondary to ineffective insulin action in the context of insulin resistance and/or inappropriate insulin secretion. Recently it has been suggested that T2D is associated with a coordinated down-regulation of the coactivator PGC1alpha and its target genes involved in mitochondrial oxidative phosphorylation.PGC1beta, a ne w coactivator homologous to PGC1alpha, which is highly expressed in heart and skeletal muscle has been recently identified. We aim to understand the role of PGC1beta; in whole body energy homeostasis and its role in the development of the Metabolic Syndrom e, and more specifically in myocardium that according to our previous research may be important for diabetes and associated heart problems. Our strategy involves a) a loss of function experiment using a PGC1beta knock-out mouse, and b) a gain of function experiment using a striated muscle (heart and skeletal muscle) transgenic PGC1beta mouse. To investigate these aims we will use a multi-approach strategy that involves in vivo phenotyping of genetically modified mouse models combined with state of the art ex vivo molecular characterisation using profiling technologies (e.g gene expression profiling, proteomic and lipidomic technologies) and advanced bioinformatics analysis. These animal models will be challenged with specific environmental interventions (hi gh fat diet, exercise) to challenge compensatory physiological mechanisms. Using these approaches we will gain insights through extensive characterisation into the global and cardiac functions of PGC1beta as integrator of specific energy homeostasis proces ses. The work will also allow, thanks to the novel multiapproach outlined, the first analysis in detail of the PGC1beta signalling and its metabolic effects.
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