A Sex-Dependent, Tropic Role for Leptin in the Somatotrope as a Regulator of POU1F1 and POU1F1-Dependent Hormones

Abstract

Pituitary somatotropes perform the key function of coordinating organismic growth and body composition with metabolic signals. However, the mechanism by which they sense and respond to metabolic signals via the adipokine leptin is unknown. The complex interplay between the heterogeneous cell types of the pituitary confounds the identification of somatotrope-specific mechanisms. Somatotropes represent 30%–40% of the anterior pituitary population and are derived from a lineage of cells that are activated by the Pit-Oct-Unc domain family domain class 1 transcription factor 1 (POU1F1) to produce GH, prolactin (PRL). and TSH. To determine the mechanism by which leptin controls somatotrope function, we used Cre-LoxP technology and fluorescence-activated cell sorting to purify and study control or leptin receptor-deleted (Lepr null) somatotropes. We report that Lepr-null somatotropes show significant reductions in GH protein (GH) and Gh mRNA. By contrast, enzyme immunoassays detected no changes in ACTH, LH, and FSH levels in mutants, indicating that the control of these hormones is independent of leptin signaling to somatotropes. Reduced TSH and PRL levels were also observed, but interestingly, this reduction occurred only in in Lepr-null somatotropes from mutant females and not from males. Consistent with the sex-specific reduction in Gh mRNA, TSH, and PRL, enzyme immunoassays detected a sex-specific reduction in POU1F1 protein levels in adult female Lepr-null somatotropes. Collectively, this study of purified Lepr-null somatotropes has uncovered an unexpected tropic role for leptin in the control of POU1F1 and all POU1F1-dependent hormones. This supports a broader role for somatotropes as metabolic sensors including sex-specific responses to leptin.