Leptin: A Metabolic Signal for the Differentiation of Pituitary Cells

Pituitary cell function is impacted by metabolic states and therefore must receive signals that inform them about nutritional status or adiposity. A primary signal from adipocytes is leptin, which recent studies have shown regulates most pituitary cell types. Subsets of all pituitary cell types express leptin receptors and leptin has been shown to exert transcriptional control through classical JAK/STAT pathways. Recent studies show that leptin also signals through post-transcriptional pathways that involve the translational regulatory protein Musashi. Mechanistically, post-transcriptional control would permit rapid cellular regulation of critical pre-existing pituitary transcripts as energy states change. The chapter will review evidence for transcriptional and/or post-transcriptional regulation of leptin targets (including Gnrhr, activin, Fshb, Gh, Ghrhr, and Pou11f1) and the consequences of the loss of leptin signaling to gonadotrope and somatotrope functions

Comprehensive Motor Testing in Fmr1-KO Mice Exposes Temporal Defects in Oromotor Coordination

Fragile X syndrome (FXS; MIM #300624), a well-recognized form of inherited human mental retardation is caused, in most cases, by a CGG trinucleotide repeat expansion in the 5\u27-untranslated region of FMR1, resulting in reduced expression of the fragile X mental retardation protein (FMRP). Clinical features include macroorchidism, anxiety, mental retardation, motor coordination, and speech articulation deficits. The Fmr1 knockout (Fmr1-KO) mouse, a mouse model for FXS, has been shown to replicate the macroorchidism, cognitive deficits, and neuroanatomical abnormalities found in human FXS. Here we asked whether Fmr1-KO mice also display appendicular and oromotor deficits comparable to the ataxia and dysarthric speech seen in FXS patients. We employed standard motor tests for balance and appendicular motor coordination, and used a novel long-term fluid-licking assay to investigate oromotor function in Fmr1-KO mice and their wild-type (WT) littermates. Fmr1-KO mice performed equally well as their WT littermates on standard motor tests, with the exception of a raised-beam task. However, Fmr1-KO mice had a significantly slower licking rhythm than their WT littermates. Deficits in rhythmic fluid-licking in Fmr1-KO mice have been linked to cerebellar pathologies. It is believed that balance and motor coordination deficits in FXS patients are caused by cerebellar neurophathologies. The neuronal bases of speech articulation deficits in FXS patients are currently unknown. It is yet to be established whether similar neuronal circuits control rhythmic fluid-licking pattern in mice and speech articulation movement in humans. © 2011 American Psychological Association

Leptin Regulation of Gonadotrope Gonadotropin-Releasing Hormone Receptors As a Metabolic Checkpoint and Gateway to Reproductive Competence

The adipokine leptin signals the body’s nutritional status to the brain, and particularly, the hypothalamus. However, leptin receptors (LEPRs) can be found all throughout the body and brain, including the pituitary. It is known that leptin is permissive for reproduction, and mice that cannot produce leptin (Lep/Lep) are infertile. Many studies have pinpointed leptin’s regulation of reproduction to the hypothalamus. However, LEPRs exist at all levels of the hypothalamic–pituitary–gonadal axis. We have previously shown that deleting the signaling portion of the LEPR specifically in gonadotropes impairs fertility in female mice. Our recent studies have targeted this regulation to the control of gonadotropin releasing hormone receptor (GnRHR) expression. The hypotheses presented here are twofold: (1) cyclic regulation of pituitary GnRHR levels sets up a target metabolic checkpoint for control of the reproductive axis and (2) multiple checkpoints are required for the metabolic signaling that regulates the reproductive axis. Here, we emphasize and explore the relationship between the hypothalamus and the pituitary with regard to the regulation of GnRHR. The original data we present strengthen these hypotheses and build on our previous studies. We show that we can cause infertility in 70% of female mice by deleting all isoforms of LEPR specifically in gonadotropes. Our findings implicate activin subunit (InhBa) mRNA as a potential leptin target in gonadotropes. We further show gonadotrope-specific upregulation of GnRHR protein (but not mRNA levels) following leptin stimulation. In order to try and understand this post-transcriptional regulation, we tested candidate miRNAs (identified with in silico analysis) that may be binding the Gnrhr mRNA. We show significant upregulation of one of these miRNAs in our gonadotrope-Lepr-null females. The evidence provided here, combined with our previous work, lay the foundation for metabolically regulated post-transcriptional control of the gonadotrope. We discuss possible mechanisms, including miRNA regulation and the involvement of the RNA binding protein, Musashi. We also demonstrate how this regulation may be vital for the dynamic remodeling of gonadotropes in the cycling female. Finally, we propose that the leptin receptivity of both the hypothalamus and the pituitary are vital for the body’s ability to delay or slow reproduction during periods of low nutrition