PREPOBEDIA

NOVEL PREP1-DEPENDENT TRANSCRIPTIONAL NETWORKS IN THE CONTROL OF INSULIN SENSITIVITY

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 Obiettivo del progetto (Objective)

'Type 2 diabets and obesity are related conditions representing major components of the metabolic syndrome and one of the most challenging health problems of this century, also because of their growing impact in childhood. Different studies have identified PPAR-gamma coactivator-1 (PGC-1alpha) as a relevant type 2 diabetes susceptibility gene playing an important role in human obesity as well. Subsequent investigations led to the discovery that p160MBP (MybBindingProtein) serves as a PGC-1alpha inhibitor. More recently, we showed that p160MBP is controlled by the Prep1 gene. Prep1 hypomorphic mice feature increase sensitivity to insulin due to raised PGC-1 alpha and decreased p160MBP levels. These mice also exhibit decreased fat body mass. Indeed, we also identified Prep1 in genetic screenings in C. Elegans and mouse ,as a major gene involved in energy homeostasis and obesity. Importantly, we have preliminary data showing Prep1 overexpression in euglycemic first-degree relatives of type 2 diabetics, which are at very high risk of diabetes. This project aims at understanding how Prep1 gene controls insulin sensitivity and determines adipogenesis, obesity and type 2 diabetes in humans. We will: 1: elucidate the molecular basis of Prep1 role in insulin sensitivity and adipogenesis through in vitro and animal model studies; 2: assess the significance of Prep1 function to insulin sensitivity in humans and the role of this gene in type 2 diabetes and its subphenotypes and in other components of the metabolic syndrome; 3: identify Prep1 target genes and establish their potential as targets for novel strategies to treat type 2 diabetes and metabolic syndrome. To achieve these objectives we have built a multidisciplinary network and gathered experts in the Prep1/p160MBP signaling, type 2 diabetes and obesity molecular biology and genetics, human and mouse genetics and high throughput analysis of gene expression and identification of target genes.'

Introduzione (Teaser)

Type 2 diabetes and obesity are considered to be the predominant metabolic syndromes of developed countries. A European consortium investigated the potential role of transcription factors in the development of these metabolic diseases.

Descrizione progetto (Article)

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.