Studying networks that control insulin sensitivity
Apart from diet, accumulating evidence indicates the involvement of the PPAR-gamma coactivator-1 (PGC-1alpha) as a susceptibility gene in type 2 diabetes and obesity. Previous work by the Prepobedia consortium members showed that the expression of the PGC-1 alpha gene inhibitor (p160MBP) is controlled by the Prep1 gene, a key factor of pancreas development and function. Transgenic animals expressing lower levels of the Prep1 gene showed an increase in sensitivity to insulin, implicating it in energy homeostasis and obesity. Aiming to advance knowledge on the Prep1 gene, the EU-funded 'Novel prep1-dependent transcriptional networks in the control of insulin sensitivity' (Prepobedia) project focused on delineating the molecular mechanisms of its function. Using specific Prep1 transgenic mice, researchers unveiled the role of the protein in lipid metabolism. RNA and chromatin immunoprecipitation (ChIP) analysis of mouse embryos identified Prep1 target genes and facilitated investigations into the impact of Prep1 absence or mutation. Results indicated that Prep1 affected, in particular, basic cellular mechanisms and important genes, including Homeobox (Hox) genes. Large-scale human genetic analysis failed to identify the Prep1 gene as a putative cause of at least some cases of type 2 diabetes or obesity. The reason was that Prep1 affected more essential functions, which obscured downstream effects. Indeed, complete absence of Prep1 was shown to drive cells to apoptosis under conditions of DNA damage in a p53-dependent way. This observation drove scientists to investigate Prep1 in cancer, revealing a novel capacity of the gene to act as a tumour suppressor. The Prepobedia study unravelled novel aspects of the Prep1 gene functions and identified its involvement in important cellular processes. Although it failed to reveal a concrete association with metabolic disorders, the generated information should enable a better understanding of how Prep1 mutations may affect human health.
