Characterization of the sex specific metabolic phenotype in very-long chain acyl-CoA dehydrogenase deficient (VLCAD-/-) mice

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Very-long chain acyl-CoA dehydrogenase deficiency is the most common disorder of mitochondrial long-chain fatty acid oxidation with an incidence of 1:50,000-1:100,000 newborns. Catabolic situations contribute to the aggravation of the symptoms and may induce severe metabolic derangement and death. Treatment for VLCAD deficiency includes avoidance of prolonged fasting and a long-chain fat-restricted and fat-modified diet in which long-chain fatty acids (LCFA) are fully or in part replaced by medium-chain triglycerides (MCT). There are no data for humans on the long-term clinical course of the disease and on the role played by sex within phenotype development. Our own results clearly indicate a sexually dimorphic response due to a defective β-oxidation machinery in the mTOR signaling leading to differences in the metabolic adaptation between male and female VLCAD-/- mice. Moreover, lipogenesis was strongly up-regulating in female VLCAD-/- mice and this effect was exacerbated by supplementation with MCT. This is of interest as MCT is widely applied as recommended therapy in the treatment of long-chain fatty acid oxidation disorders and in other diseases such as chyluria, chylotorax and cystic fibrosis as well as for absorption disorders and celiac diseases. Although such differences in patients have not yet been reported, no studies have been conducted in humans with regard to the sexually dimorphic metabolic features or signaling pathways. My hypothesis is that the concomitant effect of a deficient β-oxidation pathway and the supplementation with dietary MCT may contributes to the disturbed signaling cascade via mTOR-PPARγ axis resulting in the development of a sex specific metabolic phenotype.How MCT affects signaling pathway and the regulation of energy metabolism in a sex specific manner, is still unknown. These studies will complement our knowledge on molecular mechanisms which may be involved in the development of symptoms from a point of view not taken into consideration yet.This proposal will address the following aims:- Characterization of the sex specific metabolic phenotype - To explore the role of mTOR/ PPARγ signaling and the effect of MCT in the regulation of energy metabolismWe will, here, clarify whether i) sex may be considered an important variable to take into account in the prospective developing phenotype and ii) whether/ how a diet based on MCT affects signaling pathway and whole-body energy metabolism.