Ablation of Leptin Receptor Signaling Alters Somatotrope Transcriptome Maturation in Female Mice

Abstract

Anterior pituitary somatotropes respond to metabolic signals from the adipokine leptin to optimize functional responses to the body's nutritional state via growth hormone (GH) secretion. Molecular targets of leptin in pituitary somatotropes include GH, the GH-releasing hormone receptor (GHRHR), and, in females, the transcription factor POU1F1, all of which are dependent on leptin stimulation for expression. To identify the trophic mechanisms underlying leptin action upon somatotropes, we analyzed single-cell gene transcriptomes comparing pituitaries from a female mouse model bearing somatotropes lacking leptin receptors (LEPR-null mutants) and control pituitaries. Computational clustering of results identified all common pituitary cell types and differentially expressed genes. Mutant female somatotrope clusters showed decreased levels of Gh and Htatsf1 mRNA, which was also reduced in mutant pituitaries lacking Prop1 or POU1F1. Mutant somatotropes also showed increased expression of markers for pituitary stem and progenitor cells (eg, Sox9) and increased (1.73-6.7 fold) expression of nonsomatotrope hormones, Pomc, Lhb, Tshb, Cga, and Prl. Conversely, the mutant female Sox2-positive stem cell cluster showed decreased expression of markers for stem cells and increased expression of pituitary hormone genes. The data support a model in which the female pituitary somatotrope cell population's development and/or maintenance requires leptin trophic signals and also suggests that, in the absence of normal somatotrope maturation, pituitary stem cells are driven towards premature differentiation.

Keywords: leptin receptor; mouse; pituitary; scRNA-seq; somatotropes; stem/progenitor cells.