Editorial: Molecular Endocrinology Articles in the Spotlight for April 2012

Abstract

We are pleased to feature the following articles in this month’s issue of Molecular Endocrinology. Interestingly, the 3 articles provide novel insights into various hypothalamic pathways that regulate important aspects of reproduction and metabolism. In “GnRH Pulse Frequency-Dependent Stimulation of FSH Transcription Is Mediated via Activation of PKA and CREB,” Thompson et al provide a mechanism of GnRH pulse frequency-dependent activation of FSH involving differential activation of protein kinase A (PKA) and subsequent differential levels of cAMP-responsive element-binding protein (CREB) phosphorylation. LH gene expression is unaffected by this pathway. Furthermore, GnRH preferentially stimulates CREB phosphorylation at slow pulse frequencies, whereas PKA (the main regulator of CREB phosphorylation in the murine LT2 gonadotrope cell model) activity increases to a greater extent at slow GnRH pulse frequencies, correlating with the increase in CREB phosphorylation. Because pulsatile GnRHregulatestheexpressionandsecretionofbothFSH and LH, this work identifies the intracellular mechanism downstream of GnRH receptor activation responsible for triggering the diverse reproductive consequences of the individual gonadotropins. “Nuclear Receptor LRH-1 Induces the Reproductive Neuropeptide Kisspeptin in the Hypothalamus” by Atkin et al (freely available at http://mend.endojournals.org/) provides novel insights into the molecular mechanism controlling kisspeptin’s differential secretion. The authors show that mice lacking LRH-1 in kisspeptin neurons have reduced plasma FSH levels and corresponding defects in follicle maturation and ovulation in the ovary. These knockout mice have a prolonged estrous cycle and deliver fewer pups per litter. On a molecular level, these findings help explain why kisspeptin is differentially regulatedindistinctregionsofthehypothalamus,thearcuate and anteroventral periventricular nuclei, and have revealed an important role for LRH-1 in regulating the female reproductive axis. Groba et al’s “Hypothyroidism Compromises Hypothalamic Leptin Signaling in Mice” reveals that leptin signaling in hypothalamic arcuate neurons is compromised under hypothyroid conditions. Activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways by leptin is reduced in hypothyroid obese (ie, ob/ob) mice as evidenced by reduced phopho-STAT3 immunoreactivity and decreased SOCS3 expression. A diminished reduction in body weight and food intake in hypothyroid ob/ob mice was observed after leptin treatment. Importantly, hypothyroidism is associated with elevated transcript levels of shorter leptin receptor isoforms. Consequently, up-regulation of the shorter isoforms of the leptin receptor may represent a major mechanism by which hypothyroidism influences the leptin signaling pathway in hypothyroid mice.