PROJECT SUMMARY/ABSTRACT Metabolic health is critically dependent on tropic actions by the adipokine leptin, which programs the hypothalamus during perinatal development to receive normal metabolic signals. Anterior pituitary somatotropes are dependent on leptin for normal metabolic functions, however, the developmental timing of this leptin dependency and underlying mechanisms represent a gap in our knowledge of leptin's broader roles. The overall objective of this application is to ascertain the importance of the neonatal surge of leptin to somatotrope maturation. Our first hypothesis states that normal somatotrope maturation is dependent on perinatal leptin signals and that lack of early leptin signals alters adult somatotrope functions. Our second hypothesis states that leptin regulates somatotropes through effector pathways involving the POU1F1/PIT1 transcription factor, the mRNA translational control protein, Musashi (MSI) and regulatory microRNAs (miRNAs). Two aims will test these hypotheses: Aim 1 studies will determine how the loss of leptin signals impacts neonatal maturation of somatotropes and their metabolic functions in the adult. We will study the neonatal development of somatotropes in animal models in which leptin signals are either: 1) deleted following the somatotrope- selective ablation of Lepr exon 1; 2) blocked by a leptin antagonist during the leptin surge or 3) attenuated by maternal undernutrition. We will replace neonatal leptin in the undernourished animals to test the hypothesis that early leptin signaling is vital for neonatal maturation of somatotropes and their normal function in the adult. Aim 2 studies will identify mechanisms underlying the leptin regulation of somatotropes. These studies will use purified populations of somatotropes to determine if leptin's actions are mediated by signaling pathways that attenuate MSI-mediated repression of Pou1f1, Tsh, and Prl mRNAs. We will also study miRNA-mediated repression of Gh and Ghrhr mRNAs and will employ unbiased approaches to identify additional novel leptin-dependent mechanisms controlling somatotrope maturation. This contribution is significant because it addresses the global problem of the importance of leptin in the prevention of the metabolic dysfunction caused by maternal undernutrition, which contributes to 11% of the total global disease burden, ultimately leading to 35% of child deaths. The proposed research is conceptually innovative because it broadens our understanding of leptin actions to include cells in the anterior pituitary that are known to be important metabolic sensors, and introduces novel regulatory pathways for leptin and utilizes methodological advancements in the purification of somatotropes. The expected outcomes of the work are that (1) the findings will fully inform the field about leptin's tropic role in somatotrope maturation and function and (2) this work will provide information about mechanisms of leptin's action that may be targeted therapeutically to prevent the severe metabolic dysfunction caused by early leptin deficiency.

R01DK113776

2017-04-01

2021-03-31