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Journal of Clinical Investigation

JCI online ahead of print table of contents for May 8, 2014

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 Prevot Inserm U837, Lille, FRA Phone: +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. Klein Washington University, Saint Louis, MO, USA Phone: 314 286 2140; E-mail: rklein@dom.wustl.edu

View this article at: http://www.jci.org/articles/view/73408


TITLE: Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells

AUTHOR CONTACT: David A. Hafler Yale School of Medicine, New Haven, CT, USA Phone: 2037856351; E-mail: david.hafler@yale.edu


David M. Kofler Yale 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


TITLE: Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction

AUTHOR CONTACT: Thorsten Mempel Massachusetts General Hospital & Harvard Medical School, Charlestown, MA, USA Phone: 617-724-4596; E-mail: tmempel@mgh.harvard.edu

View this article at: http://www.jci.org/articles/view/66375

TITLE Inhibition of ER stress–associated IRE-1/XBP-1 pathway reduces leukemic cell survival

AUTHOR CONTACT: Chih-Chi Andrew Hu H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA Phone: 813-745-4167; E-mail: chih-chi.hu@moffitt.org


Juan R. Del Valle H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA Phone: 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 Zhang University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Phone: 608-263-1147; E-mail: zhang@oncology.wisc.edu

View this article at: http://www.jci.org/articles/view/74182


TITLE: KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria

AUTHOR CONTACT: Hiroyuki Sasamura Keio University, Tokyo, JPN Phone: 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


TITLE: Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

AUTHOR CONTACT: Martin Steinhoff UCD (University College Dublin), Dublin, IRL Phone: +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


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