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JCI table of contents: May 24, 2007

JCI Journals

EDITOR'S PICK

Stuck on you: CEACAM6 helps E. coli stick to intestinal lining in Crohn's disease

In Crohn's disease, the lining of the small intestine is abnormally colonized by E. coli organisms that are able to adhere to and invade intestinal epithelial cells. In a study appearing online on May 24 in advance of publication in the June print issue of the Journal of Clinical Investigation, Arlette Darfeuille-Michaud and colleagues from Université d'Auvergne, France, show that the adherent-invasive E. coli (AIEC) adhere to a region of intestinal epithelial cells known as the brush border in patients with Crohn's disease, but not in healthy individuals. They show that this adhesion is dependent on the expression of the receptor CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule 6) on the surface of the epithelial cells. They go on to show that CEACAM6 expression is increased in Crohn's disease patients after infection with AIEC bacteria, indicating that this organism can promote its own colonization in individuals with Crohn's disease. The authors conclude that CEACAM6 expression in individuals with inflammatory bowel disease could be used as a diagnostic marker for Crohn's disease.

TITLE: CEACAM6 acts as a receptor for adherent-invasive E. coli supporting ileal mucosa colonization in Crohn disease

AUTHOR CONTACT:
Arlette Darfeuille-Michaud
Université d'Auvergne, Clermont-Ferrand, France.
Phone : 33-4-73-17-79-97; Fax: 33-4-73-17-83-71; E-mail: arlette.darfeuille-michaud@u-clermont1.fr

View the PDF of this article at: https://www.the-jci.org/article.php?id=30504


METABOLIC DISEASE

PPARgamma is required for the full effect of antidiabetic drugs

The molecule known as PPARgamma is required for the development of fat cells and is the target of antidiabetic drugs known as thiazolidinediones (TZDs). In a study appearing online on May 24 in advance of publication in the June print issue of the Journal of Clinical Investigation, Andrea Hevener and colleagues from UCSD report the unexpected finding that inactivation of PPARgamma in macrophages resulted in the development of insulin resistance in the livers of lean mice fed a normal diet, as well as impaired insulin signaling in fatty tissue, liver, and muscle. The authors went on to show that insulin resistance was even further impaired in these animals when they were fed a high-fat diet and the animals were only partially responsive to treatment with TZDs. The study reveals the essential role for PPARgamma in macrophages for the maintenance of insulin action in the whole body as well as in mediating the antidiabetic effects of TZDs.

TITLE: Macrophage PPARgamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones

AUTHOR CONTACT:
Andrea Hevener
University of California, Los Angeles, Los Angeles, California, USA.
Phone : (310) 794-7555 ; E-mail: ahevener@mednet.ucla.edu

Jerrold M. Olefsky or Christopher K. Glass
University of California, San Diego, California, USA.
E-mail: jolefsky@ucsd.edu (J. Olefsky)
E-mail: ckg@ucsd.edu (C.K. Glass)

Mercedes Ricote
Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
Phone: 34-91-4531200; Fax: 34-91-4531245; E-mail: mricote@cnic.es

View the PDF of this article at: https://www.the-jci.org/article.php?id=31561


METABOLIC DISEASE

Mind over liver: Resistin's action in brain linked to liver insulin resistance

Resistin is a small protein secreted by the immune cells monocytes and macrophages, and has been linked to insulin resistance, atherosclerosis, and inflammation. Recently, studies in mice have shown that resistin is present in the mouse hypothalamus and that it is capable of activating specific neurons. These and other studies have highlighted the importance of a brain-liver circuit in controlling glucose and insulin handling in the body.

In a study appearing online on May 24 in advance of publication in the June print issue of the Journal of Clinical Investigation, Luciano Rossetti and colleagues from Yeshiva University found that resistin delivery to the hypothalamus in mice stimulated changes in the circulating levels of hormones that help regulate glucose production, in a manner independent of glucose production itself. Conversely, administration of specific anti-resistin antibodies markedly diminished the ability of circulating resistin to increase glucose production. The study extends our understanding of resistin physiology by showing that resistin exerts its potent actions on the liver partly via its action within the hypothalamus. Secondly, resistin exerts proinflammatory influence on the liver through both peripheral and central mechanisms. The authors suggest that the action of resistin in the hypothalamus may contribute to high blood glucose levels in type 2 diabetics.

TITLE: Hypothalamic resistin induces hepatic insulin resistance

AUTHOR CONTACT:
Luciano Rossetti
Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, USA.
Phone : (718) 430-4118; Fax : (718) 430-8557; E-mail : rossetti@aecom.yu.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=30440


DEVELOPMENT

Gene Gas1 is involved in severe craniofacial malformations

Holoprosencephaly (HPE) is caused by the failure of an embryo's forebrain to divide to form the distinct left and right halves of the brain, causing defects in the development of the face and in the structure and function of the brain. The most severe form of facial defects is cyclopia, in which only a single eye develops in the region normally occupied by the bridge of the nose. Mutations in the sonic hedgehog gene (Shh) have been established to cause HPE in both humans and mice. In a study appearing online on May 24 in advance of publication in the June print issue of the Journal of Clinical Investigation, Martyn Cobourne and colleagues from King's College London Dental Institute report that the gene Gas1 interacts with Shh and that mice lacking Gas1 exhibit a form of HPE.

Gas1 encodes a membrane glycoprotein that is repressed in response to Shh. Cobourne and colleagues found that mice with a targeted Gas1 deletion had underdeveloped faces, fused teeth, cleft palates, and severe ear defects, however their forebrains remained intact. These effects were associated with a partial loss of Shh signaling, suggesting that Gas1 is involved in Shh signaling in the early development of the face. The authors went on to show that loss of a single Shh allele in Gas1-/- mice exacerbated the facial deformities, providing evidence that Shh and Gas1 interact. The study suggests that GAS1 in humans may act as a modifier of other genes in some human craniofacial malformations.

TITLE: Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog

AUTHOR CONTACT:
Martyn T. Cobourne
King's College London, London, United Kingdom.
Phone : 44-2071884432; Fax: 44-2071884415; E-mail: martyn.cobourne@kcl.ac.uk

View the PDF of this article at: https://www.the-jci.org/article.php?id=32032


PHYSIOLOGY

NF-kappaB activation is key to acute pancreatitis

Inflammation of the pancreas (pancreatitis), which is due to the breakdown of pancreatic tissue by its own enzymes, is a common clinical problem. Activation of the signaling pathway involving NF-kappaB and the inhibitor of NF-kappaB (IKK), resulting in the expression of proinflammatory molecules, is a major event in acute pancreatitis. However, the consequences of this activation on the onset and progression of pancreatitis remain unclear. Two separate studies appearing online on May 24 in advance of publication in the June print issue of the Journal of Clinical Investigation, investigate the role of this signaling pathway in pancreatitis in mice.

In the first study, Thomas Wirth and colleagues from the University of Ulm, Germany, examined mice bred to only express IKK2 in pancreatic acinar cells. They found that constitutive IKK2 expression was sufficient to induce acute pancreatitis via the activation of known NF-kappaB target genes. In the second study, Roland Schmid and colleagues from the Technical University of Munich, Germany, investigated the role of a subunit of NF-kappaB called RelA/p65 in acute pancreatitis. Selective truncation of the rela gene in pancreatic cells led to both a severe injury of the acinar cells as well as systemic complications including lung and liver damage. The authors went on to show that expression of the protective pancreas-specific protein PAP1 was dependent on RelA/p65 and able to reduce the extent of pancreatic tissue necrosis in the rela mice. The results provide evidence of a role for RelA/p65 in the protection of pancreatic acinar cells against cell death, via the upregulation of PAP1. Together, the two studies identify the IKK/NF-kappaB pathway in acinar cells as being key to the development of experimental pancreatitis and the major factor in the inflammatory response that is typical of this disease.

TITLE: Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo

AUTHOR CONTACT:
Thomas Wirth
University of Ulm, Ulm, Germany.
Phone : 49-0-731-50023270; Fax : 49-0-731-50022892; E-mail: thomas.wirth@uni-ulm.de

View the PDF of this article at: https://www.the-jci.org/article.php?id=30876

RELATED MANUSCRIPT:

TITLE: Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis

AUTHOR CONTACT:
Roland M. Schmid
Technical University of Munich, Munich, Germany.
Phone : 49-89-4140-2250; Fax: 49-89-4140-4871; E-mail: roland.schmid@lrz.tu-muenchen.de

View the PDF of this article at: https://www.the-jci.org/article.php?id=29882

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