Ovulation is triggered by a cyclical modulation of gonadotropes into a hyperexcitable state

Gonadotropes in the anterior pituitary gland are essential for fertility and provide a functional link between the brain and the gonads. To trigger ovulation, gonadotrope cells release massive amounts of luteinizing hormone (LH). The mechanism underlying this remains unclear. Here, we utilize a mouse model expressing a genetically encoded Ca2+ indicator exclusively in gonadotropes to dissect this mechanism in intact pituitaries. We demonstrate that female gonadotropes exclusively exhibit a state of hyperexcitability during the LH surge, resulting in spontaneous [Ca2+]i transients in these cells, which persist in the absence of any in vivo hormonal signals. L-type Ca2+ channels and transient receptor potential channel A1 (TRPA1) together with intracellular reactive oxygen species (ROS) levels ensure this state of hyperexcitability. Consistent with this, virus-assisted triple knockout of Trpa1 and L-type Ca2+ subunits in gonadotropes leads to vaginal closure in cycling females. Our data provide insight into molecular mechanisms required for ovulation and reproductive success in mammals

Funktionelle Rolle(n) der Gonadotropine im Leber- und Knochenstoffwechsel

Die Gonadotropin-releasing hormone (GnRH) Neurone im Hypothalamus steuern die Reproduktionsachse der Säugetiere. Das GnRH wird pulsatil in das hypophysäre Pfortaderblut freigesetzt und stimuliert die Synthese und Sekretion der Gonadotropine, d.h. des Follikel-stimulierenden Hormons (FSH) und des luteinisierenden Hormons (LH), in den gonadotropen Zellen des Hypophysenvorderlappens, um die Gonadenfunktion kontrollieren. Zahlreiche Studien in den letzten Jahrzehnten haben die funktionelle Rolle der Gonadotropine im Rahmen der Fortpflanzungsphysiologie untersucht. Jüngste Studien an Tiermodellen deuten allerdings darauf hin, dass FSH und LH auch physiologische Vorgänge außerhalb der Reproduktionsachse, wie z.B. den Leber- und Knochenstoffwechsel, beeinflussen. Wie genau die Gonadotropine auf extra-gonadale Organe wirken, ist bisher nur unzureichend untersucht. Um die Rolle von FSH und LH systemisch zu analysieren haben wir ein neues Mausmodell generiert und die gonadotropen Zellen in adulten Tieren akut mittels Diphtherie-Toxin ablatiert. Neben einem profunden Hypogonadismus führt der Verlust der gonadotropen Zellen bei weiblichen Mäusen zu Fettleibigkeit, Glukoseintoleranz, Lebersteatose und Knochenschwund. Wir zeigen, dass diese Phänotypen mit Ausnahme der Lebersteatose indirekt durch das Fehlen von Geschlechtshormonen verursacht werden. Eine erhöhte Gonadotropinfreisetzung durch gezielte pharmakogenetische Aktivierung der gonadotropen Zellen verbessert die hepatische Steatose. Eine Verbesserung der hepatischen Steatose kann auch durch FSH-Injektion erreicht werden. Durch konditionalen Knock-out des FSH-Rezeptors in der Hypophyse mit Hilfe eines viralen CRISPR/Cas9-Ansatzes konnten wir schließlich nachweisen, dass eine parakrine Signalübertragung zu den kortikotropen Zellen des Hypophysenvorderlappens für die Verhinderung der Entwicklung von Lebersteatose unerlässlich ist. Zusammengefasst zeigen diese Ergebnisse, dass FSH neben seiner klassischen Rolle in der Reproduktionsphysiologie weitere wichtige Funktionen erfüllt. Die hier identifizierte parakrine Signalübertragung zwischen gonadotropen und kortikotropen Zellen dokumentiert zum ersten Mal eine Kommunikation unterschiedlicher Hormon-sezernierender Zelltypen in der adulten Hypophyse. Da die kortikotropen Zellen in der menschlichen Hypophyse ebenfalls den FSH-Rezeptor exprimieren, könnte dessen Aktivierung ein potenzielles therapeutisches Ziel darstellen.Gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus regulate the mammalian reproductive axis. GnRH is released in pulses into the hypophyseal portal blood to stimulate both the synthesis and secretion of gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), from gonadotrope cells in the anterior pituitary gland. FSH and LH in turn control gonadal function. Many efforts have been made over the past decades to dissect the functional aspects of gonadotropin signaling. However, these studies have almost exclusively focused on reproductive physiology. Interestingly, recent studies in animal models indicate that FSH and LH may also influence physiological processes outside of the reproductive axis, such as liver and bone metabolism. Exactly how the gonadotropins act on extragonadal organs is, however, not well understood. To analyze the role of FSH and LH systemically, we generated a new mouse model and acutely ablated the gonadotrope cells in adult animals using diphtheria toxin. In addition to profound hypogonadism, the loss of gonadotrope cells in female mice leads to obesity, glucose intolerance, hepatic steatosis, and bone loss. We show that these phenotypes, with the exception of hepatic steatosis, are indirectly caused by the lack of sex hormones. We also demonstrate that increased gonadotropin release through targeted pharmacogenetic activation of gonadotrope cells improves hepatic steatosis. An improvement in hepatic steatosis can also be achieved by FSH administration. Finally, by conditionally knocking out the FSH receptor in the pituitary gland using a viral CRISPR/Cas9 approach, we were able to demonstrate that paracrine signaling to the corticotrope cells of the anterior pituitary gland is essential for preventing the development of hepatic steatosis. Taken together, these results show that FSH exerts other important functions in addition to its classic role in reproductive physiology. The identified paracrine signaling between gonadotrope and corticotrope cells is the first to document communication between different hormone-secreting cell types in the adult pituitary gland. Since the corticotropes in the human pituitary also express the FSH receptor, its activation could represent a potential therapeutic target

Ovulation is triggered by a cyclical modulation of gonadotropes into a hyperexcitable state

Summary: Gonadotropes in the anterior pituitary gland are essential for fertility and provide a functional link between the brain and the gonads. To trigger ovulation, gonadotrope cells release massive amounts of luteinizing hormone (LH). The mechanism underlying this remains unclear. Here, we utilize a mouse model expressing a genetically encoded Ca2+ indicator exclusively in gonadotropes to dissect this mechanism in intact pituitaries. We demonstrate that female gonadotropes exclusively exhibit a state of hyperexcitability during the LH surge, resulting in spontaneous [Ca2+]i transients in these cells, which persist in the absence of any in vivo hormonal signals. L-type Ca2+ channels and transient receptor potential channel A1 (TRPA1) together with intracellular reactive oxygen species (ROS) levels ensure this state of hyperexcitability. Consistent with this, virus-assisted triple knockout of Trpa1 and L-type Ca2+ subunits in gonadotropes leads to vaginal closure in cycling females. Our data provide insight into molecular mechanisms required for ovulation and reproductive success in mammals

Intra-pituitary follicle-stimulating hormone signaling regulates hepatic lipid metabolism in mice

International audienceInter-organ communication is a major hallmark of health and is often orchestrated by hormones released by the anterior pituitary gland. Pituitary gonadotropes secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to regulate gonadal function and control fertility. Whether FSH and LH also act on organs other than the gonads is debated. Here, we find that gonadotrope depletion in adult female mice triggers profound hypogonadism, obesity, glucose intolerance, fatty liver, and bone loss. The absence of sex steroids precipitates these phenotypes, with the notable exception of fatty liver, which results from ovary-independent actions of FSH. We uncover paracrine FSH action on pituitary corticotropes as a mechanism to restrain the production of corticosterone and prevent hepatic steatosis. Our data demonstrate that functional communication of two distinct hormone-secreting cell populations in the pituitary regulates hepatic lipid metabolism