Investigation of mechanisms of action for DLK1 on GnRH hypothalamic secretion and metabolic pathways

Abstract

Rare inactivating allelic variants in the MKRN3 and DLK1 genes have been identified as monogenic causes of central precocious puberty (CPP). Patients with familial CPP and DLK1 mutations have shown a higher frequency of metabolic alterations in adulthood. Similar to this finding, studies have shown that Dlk1-deficient mice also have metabolic alterations. The association between puberty and metabolism, both under normal and pathological conditions, is well evidenced, but the molecular mechanisms through which this association occurs are still poorly known. The objective of this project is to evaluate the involvement of DLK1 in puberty of central origin and its association with metabolic effects in patients with CPP without association with syndromic condition. For this, the transcriptomes of patients with CPP carrying inactivating mutations in the DLK1 gene will be evaluated using the global RNA sequencing technique in samples of whole blood and adipose tissue, and the transcriptome of the knockout of the Dlk1 gene in murine hypothalamic cells will also be evaluated. Additionally, in vitro assays will be performed to determine which mechanisms associate DLK1 with GnRH secretion and metabolism. The results of this work will help both in understanding the mechanisms of the association between puberty and metabolism, and in recognizing the profile of patients with mutations in the DLK1 gene, with the aim of preventing future metabolic diseases in patients with CPP. (AU)