Food intake and energy expenditure are the main components of energy balance and both are regulated by the central nervous system (CNS). Failure of these homeostatic mechanisms results in deregulation of lipid and glucose metabolism leading to insulin resistance and obesity.
Defects in energy homeostasis may impact neuronal survival and accelerate the neurodegenerative process associated with ageing. The CNS receives peripheral nutritional signals that acting on specific hypothalamic nuclei and controls the energy balance. PGC1a is a coactivator of several transcription factors, involved in thermogenesis, mitochondrial biogenesis and energy expenditure; and its genetic ablation generates lesions in the striatal region of the brain.
My project will focus on P GC1ß, a new coactivator homologous to PGC1a, which is highly expressed in heart, skeletal muscle and relevant for this proposal also in brain. Our aim is to understand the role of PGC1ß in the brain lipid and glucose homeostasis and their pathological states such as insulin resistance, obesity, neuronal death and ageing.
I will investigate these using two complementary strategies:
- I will characterize the specific pattern of PGC1ß gene expression in the mouse brain using a PGC1ß promoter driven GFP transgenic mouse model and
- I will characterize the effects of PGC1ß in brain using the PGC1ßKO and if necessary neuron/nuclei specific PGC1ßKO mouse models using a Cre/lox approach.
To investigate these aims we will use genetically modified mouse models combined with
- transcriptomic profiling,
- cerebral imaging analysis, complemented with
- intracerebral stereotaxic injections of viruses over-expressing PGC1a and ß and d) electrophysiologic techniques.
The relevance of the outcome of the study will be the extensive characterization of the role of PGC1ß on insulin sensitivity and PGC1ß mediated ageing effects on neuronal survival.
Fields of science
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