EDITOR'S PICK: Slim down by targeting the hormone uroguanylin
The number of people who are obese and suffer one or more of its associated health problems (including type 2 diabetes) is escalating dramatically. Researchers are seeking to identify new targets for therapeutics that could limit appetite and thereby obesity. A team of researchers, led by Scott Waldman, at Thomas Jefferson University, Philadelphia, has now uncovered one such potential target by studying the molecular control of appetite in mice.
In the study, Waldman and colleagues found that nutrient intake by mice caused cells in their gut to secrete the precursor of the hormone uroguanylin (prouroguanylin) into the blood. This travelled around the blood and was converted to uroguanylin in a region of the brain known as the hypothalamus, which is well known to be involved in decreasing appetite. The active uroguanylin was then found to bind to proteins on nerve cells known as GUCY2C receptors, triggering a cascade of events that led to decreased food intake. The data generated by Waldman and colleagues leads them to suggest that targeting this uroguanylin-GUCY2C pathway might provide a new approach to controlling appetite, obesity, and its associated health problems, something that Randy Seeley and Matthias Tschöp, at the University of Cincinnati, Cincinnati, concur with in an accompanying commentary.
TITLE: A uroguanylin-GUCY2C endocrine axis regulates feeding in mice
AUTHOR CONTACT:
Scott A. Waldman
Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Phone: 215.955.6086, Fax: 215.955.7006, E-mail: Scott.Waldman@jefferson.edu.
View this article at: http://www.jci.org/articles/view/57925?key=2be559b99b106f75a4da
ACCOMPANYING COMMENTARY
TITLE: Uroguanylin: how the gut got another satiety hormone
AUTHOR CONTACT:
Randy J. Seeley
University of Cincinnati, Cincinnati, Ohio, USA.
Phone: 513.558.6665; Fax: 513.558.0187; E-mail: randy.seeley@uc.edu.
View this article at: http://www.jci.org/articles/view/58297?key=56e135d075ddebca6ffe
EDITOR'S PICK: Linking Parkinson disease and fat levels in the blood
Parkinson disease (PD) is a relatively common neurodegenerative disorder, affecting 1-2% of the world's population over the age of 65 years. About 5-10% of PD cases are inherited, and mutations in the Parkin gene are a common cause of familial PD. Michael Sack and colleagues, at the National Institutes of Health, Bethesda, have now identified a new function for the protein templated by the Parkin gene, it regulates fat uptake from the blood by liver cells and thereby fat levels in the blood. Furthermore, they determine that it does this by regulating the level of expression of the fat transporter CD36 on liver cells. Future studies will determine whether perturbations in this function of parkin contribute to the development of PD caused by mutations in the Parkin gene.
As noted in an accompanying commentary, by Nada Abumrad, at Washington University School of Medicine, St Louis, and Darren Moore, at Ecole Polytechnique Fédérale de Lausanne, Switzerland, the additional observation of Sack and colleagues that levels of parkin protein are increased in mice fed a high-fat diet, provides support for the emerging idea that dietary fat intake can impact susceptibility to PD.
TITLE: Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells
AUTHOR CONTACT:
Michael N. Sack
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301.402.9259; Fax: 301.480.4599; E-mail: sackm@nhlbi.nih.gov.
View this article at: http://www.jci.org/articles/view/44736?key=a9aa051cef209eafac0e
ACCOMPANYING COMMENTARY TITLE: Parkin reinvents itself to regulate fatty acid metabolism by tagging CD36
AUTHOR CONTACT:
Nada A. Abumrad
Washington University School of Medicine, St Louis, Missouri, USA.
Phone: 314.747.0348; Fax: 314.444.3432; E-mail: nabumrad@wustl.edu.
View this article at: http://www.jci.org/articles/view/59219?key=78216f975ade76ff66ad
NEUROBIOLOGY: Support cells in the gut: an inefficient source of new nerves
The enteric nervous system (ENS) is a subdivision of the nervous system that controls many of the functions of the gastrointestinal system, including the contraction and relaxation of the gut wall muscles that moves food through the gut. Some individuals are born without bundles of ENS nerves in segments of their large intestine (e.g., those with Hirschsprung disease), while others lose ENS nerves later in life (e.g., as a complication of Chagas disease). Some researchers are seeking to develop cell-replacement therapies for such individuals. So many problems confront the use of stem cells that learning how to activate nerve precursors in a patient's own bowel is an attractive alternative. It has been suggested that glial cells in the gut — which "glue" together the various components of the ENS; nurture, defend, and insulate the nerves; and clean up debris should nerves die — could be useful nerve precursors in this context. However, two independent reports — one by Sean Morrison and colleagues, at the University of Michigan, Ann Arbor; and one by a team of researchers led by Vassilis Pachnis, at the National Institute for Medical Research, United Kingdom — now provide compelling evidence that although glial cells in the gut are capable of giving rise to nerves in the gut of adult mice, they can only do so under certain restricted conditions. As noted in an accompanying commentary by Michael Gershon, at Columbia University, New York, the data in these two reports make it clear that turning glial cells in the gut into nerves of the ENS in situ is not going to be easy.
TITLE: Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut
AUTHOR CONTACT:
Sean J. Morrison
University of Michigan, Ann Arbor, Michigan, USA.
Phone 734.647.6261; Fax: 734.615.8133; E-mail: seanjm@umich.edu.
View this article at: http://www.jci.org/articles/view/58186?key=d9b1b5bb26283ebcd543
ACCOMPANYING MANUSCRIPT
TITLE: Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury
AUTHOR CONTACT:
Vassilis Pachnis
Medical Research Council National Institute for Medical Research, London, United Kingdom.
Phone: +44.2088162113; Fax: +44.2088162109; E-mail: vpachni@nimr.nerc.ac.uk.
View this article at: http://www.jci.org/articles/view/58200?key=0ee2c787e0fddc8b2aec
ACCOMPANYING COMMENTARY
TITLE: Behind an enteric neuron there may lie a glial cell
AUTHOR CONTACT:
Michael D. Gershon
Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Phone: 212.305.3447; Fax: 212.305.3973; E-mail: mdg4@columbia.edu.
View this article at: http://www.jci.org/articles/view/59573?key=cd3dc440f5d3713cb4ed
REPRODUCTIVE BIOLOGY: You can't outFOX(O1) spermatogonial stem cells
Sperm develop in the testes from spermatogonial stem cells. The key to spermatogonial stem cell function is that when they divide they can both self-renew and/or form more specialized cells (i.e., they can differentiate). If the molecular mechanisms regulating the self-renewal and differentiation of spermatogonial stem cells could be defined, they could provide insight into diseases associated with abnormal spermatogonial stem cell function, including some forms of male infertility and many cases of testicular cancer. In this context, Diego Castrillon and colleagues, at the University of Texas Southwestern Medical Center, Dallas, have now determined that the gene regulatory factor Foxo1 is required in mice to maintain numbers of spermatogonial stem cells and to ensure that they begin differentiating into sperm cells. Future studies will examine the molecular pathways up and downstream of Foxo1 in the hope that this will provide further insight into causes of male infertility and testicular cancer, common but poorly understood conditions.
TITLE: Foxo1 is required in mouse spermatogonial stem cells for their maintenance and the initiation of spermatogenesis
AUTHOR CONTACT:
Diego H. Castrillon
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214.648.4032; Fax: 214.648.7355; E-mail: diego.castrillon@utsouthwestern.edu.
View this article at: http://www.jci.org/articles/view/57984?key=13552cff6074fd68af8e
METABOLIC DISEASE: If at first you don't succeed (in making a human pancreatic beta-cell line), try, try again
Type 1 and type 2 diabetes arise as a result of loss of function of the beta-cells in the pancreas. Studies of human pancreatic beta cells are an important part of learning more about the mechanisms underlying diabetes and developing new therapeutics. Such studies are hampered, however, by the fact that isolating human pancreatic beta cells is extremely difficult and that despite decades of attempts by many, human pancreatic beta cell lines that retain the characteristics of the primary cells remain unavailable. However, a team of researchers — led by Raphael Scharfmann at Hôpital Necker, France; and Philippe Ravassard, at Université Pierre et Marie Curie-Paris 6, France — has now finally succeeded in generating a cell line from human pancreatic beta cells that maintains most of the characteristics of primary mature beta cells. As noted by the authors and, in an accompanying commentary, Gordon Weir and Susan Bonner-Weir — at the Joslin Diabetes Center, Boston — this cell line provides a unique tool for advancing understanding of the mechanisms underlying diabetes and for facilitating the discovery of drugs to treat diabetes and the development of beta cell–replacement therapies.
TITLE: A genetically engineered human pancreatic beta-cell line exhibiting glucose-inducible insulin secretion
AUTHOR CONTACT:
Raphael Scharfmann
INSERM U845, Université Paris Descartes, Hôpital Necker, Paris, France.
Phone: 33.1.40615565; Fax: 33.1.43.06.04.43; E-mail: raphael.scharfmann@inserm.fr.
Philippe Ravassard
Université Pierre et Marie Curie-Paris 6, UMRS 975, Paris, France.
Phone: 33.1.57274575; Fax: 33.1.42.17.53.33; E-mail: philippe.ravassard@upmc.fr.
View this article at: http://www.jci.org/articles/view/58447?key=b956626e6b894aa3f213
ACCOMPANYING COMMENTARY
TITLE: Finally! A human pancreatic beta-cell line
AUTHOR CONTACT:
Gordon C. Weir
Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.732.2581 Fax: 617.732.2650; E-mail: gordon.weir@joslin.harvard.edu.
View this article at: http://www.jci.org/articles/view/58899?key=e7de61e9897841876165
ENDOCRINOLOGY: Brain power: how insulin indirectly acts on the liver
The hormone insulin reduces levels of sugar (glucose) in the blood. It does this in several different ways, chief among them inhibiting glucose production in the liver and enhancing glucose uptake by the liver. Studies in rodents suggest that insulin's effects on the liver are mediated both directly (i.e., insulin acts on the cells of the liver) and indirectly, with insulin acting via neurons in the brain to decrease glucose production. Whether insulin has similar indirect effects in humans and large mammals, such as dogs, remains controversial. Now, a team of researchers, led by Christopher Ramnanan, at Vanderbilt University School of Medicine, Nashville, has determined that in dogs, insulin can mediate effects on the liver via effects on the brain. However, the effects were modest and worked by enhancing glucose uptake rather than reducing glucose production. In an accompanying commentary, Barry Levin and Robert Sherwin suggest that insulin's effects on the liver via the brain might not have much of a role in healthy individuals but could assume great significance in individuals with type 2 diabetes.
TITLE: Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs
AUTHOR CONTACT:
Christopher J. Ramnanan
Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Phone: 615.322.7014; Fax: 615.343.0490; E-mail: chris.ramnanan@vanderbilt.edu.
View this article at: http://www.jci.org/articles/view/45472?key=1e7a0387fba0faa31c16
ACCOMPANYING COMMENTARY TITLE: Peripheral glucose homeostasis: does brain insulin matter?
AUTHOR CONTACT:
Barry E. Levin
Veterans Administration Medical Center, East Orange, New Jersey, USA.
Phone: 973.676.1000, ext. 1442; Fax: 973.395.7112; E-mail: levin@umdnj.edu.
View this article at: http://www.jci.org/articles/view/59653?key=3def44194053edff866d
Journal
Journal of Clinical Investigation