Leptin-dependent regulation of reproduction
Individuals that lack the adipose-derived hormone leptin fail to complete puberty and are infertile. Leptin-deficient mice recapitulate human phenotypes; however, it is not clear how leptin and leptin signaling impact the reproductive axis. In this issue of the Journal of Clinical Investigation, Vincent Prevot and colleagues at INSERM U837 evaluated leptin deficient animals and determined that leptin acts directly on neurons in the preoptic region of the hypothalamus that synthesize nitric oxide to regulate peripheral levels of leutinizing hormone (LH), which is essential for reproduction. Administration of leptin increased neuronal production of nitric oxide synthase, while deletion or pharmacological inhibition of NOS blocked leptin-induced LH release in mice. Mathematical models indicated that leptin action in the preoptic region leads to a build-up of NO that reaches a level that is critical for the induction and release of gonadotropin-releasing hormone (GnRH) and subsequent LH secretion by the pituitary gland. This study demonstrates that leptin communicates the status of peripheral energy stores to GnRH-releasing neurons via the preoptic hypothalamus to regulate fertility.
TITLE: Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction
AUTHOR CONTACT: Vincent PrevotInserm U837, Lille, FRAPhone: +33 612-90-38-76; E-mail: vincent.prevot@inserm.fr
View this article at: http://www.jci.org/articles/view/65928
Female susceptibility to CNS autoimmunity linked to sphingosine-1 phosphate receptor
Relapsing-remitting multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is defined by extensive neuronal demyelination and enhanced blood brain barrier (BBB) permeability. There is a strong sex bias in MS patients, with 3 to 4 female patients for every affected male. The female bias is recapitulated in SLJ mice with experimental autoimmune encephalitis (EAE), a commonly used MS model. In this issue of the Journal of Clinical Investigation, Robyn Klein and colleagues at Washington University performed whole transcriptome analysis of transcripts collected from EAE-susceptible CNS regions in naïve SJL mice and determined that female SJL mice express dramatically higher levels of the sphingosine-1 phosphate receptor S1PR2 compared to male animals. Expression and activity of S1PR2 were associated with endothelial barrier dysfunction, which enhanced BBB permeability and the loss of immune privilege. Pharmacological inactivation of S1PR2 signaling attenuated BBB permeability and EAE severity. Importantly, female MS patients also exhibited increased expression of S1PR2 in the CNS vasculature during periods of MS-associated CNS autoimmunity, indicating that S1PR2 may be a suitable therapeutic target in humans.
TITLE: Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility
AUTHOR CONTACT: Robyn S. KleinWashington University, Saint Louis, MO, USAPhone: 314 286 2140; E-mail: rklein@dom.wustl.edu
View this article at: http://www.jci.org/articles/view/73408
IMMUNOLOGY
TITLE: Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells
AUTHOR CONTACT: David A. HaflerYale School of Medicine, New Haven, CT, USAPhone: 2037856351; E-mail: david.hafler@yale.edu
Or
David M. KoflerYale School of Medicine, New Haven, CT, USA Phone: 203.785.5947; Fax: 203.785.2238; E-mail: david.kofler@yale.edu
View this article at: http://www.jci.org/articles/view/72973
ONCOLOGY
TITLE: Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction
AUTHOR CONTACT: Thorsten MempelMassachusetts General Hospital & Harvard Medical School, Charlestown, MA, USAPhone: 617-724-4596; E-mail: tmempel@mgh.harvard.edu
View this article at: http://www.jci.org/articles/view/66375
TITLEInhibition of ER stress–associated IRE-1/XBP-1 pathway reduces leukemic cell survival
AUTHOR CONTACT: Chih-Chi Andrew HuH. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USAPhone: 813-745-4167; E-mail: chih-chi.hu@moffitt.org
Or
Juan R. Del ValleH. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USAPhone: 813.745.4167; Fax: 813.745.1328; Email: Juan.DelValle@moffitt.org
View this article at: http://www.jci.org/articles/view/73448
TITLE: Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm
AUTHOR CONTACT: Jing ZhangUniversity of Wisconsin School of Medicine and Public Health, Madison, WI, USAPhone: 608-263-1147; E-mail: zhang@oncology.wisc.edu
View this article at: http://www.jci.org/articles/view/74182
NEPHROLOGY
TITLE: KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria
AUTHOR CONTACT: Hiroyuki SasamuraKeio University, Tokyo, JPNPhone: 81-3-5363-3796; Fax: 81-3-3359-2745; E-mail: sasamura@a8.keio.jp
View this article at: http://www.jci.org/articles/view/69557
NEUROSCIENCE
TITLE: Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus
AUTHOR CONTACT: Martin SteinhoffUCD (University College Dublin), Dublin, IRLPhone: +353 1 716 6261; Fax: +353 1 716 6265; E-mail: Martin.Steinhoff@ucd.ie
View this article at: http://www.jci.org/articles/view/67323