JCI online early table of contents: Oct. 9, 2008

One role for the proteins on the tongue that sense bitter tasting substances, type 2 taste receptors (T2Rs), is to limit ingestion of these substances, as a large number of natural bitter compounds are known to be toxic. T2Rs are also found in the gut, and it has been suggested that there they have a similar role to their function in the mouth (i.e., they might limit intestinal toxin absorption). Data to support this idea has now been generated in mice by Timothy Osborne and colleagues, at the University of California, Irvine.

By supplementing the food that mice eat with the drugs lovastatin and ezetimibe (L/E), it is possible to reduce the amount of cholesterol that they take up, and they are therefore considered to be consuming a low-cholesterol diet. Such a diet increases the activity of the protein SREBP-2 in the gut. In this study, SREBP-2 was shown to directly induce the expression of T2Rs in cultured mouse intestinal cells as well as in the intestine of mice consuming food supplemented with L/E. In addition, SREBP-2 was shown to directly enhance T2R-induced secretion of the intestinal peptide cholecystokinin in both the cultured mouse intestinal cells and mice consuming food supplemented with L/E. As low-cholesterol diets are naturally composed of high amounts of plant matter that is likely to contain dietary toxins, and one function of cholecystokinin is to decrease food intake, the authors suggest that SREBP-2–induced expression of T2Rs might provide a mechanism both to inform the gut that food-borne toxins could be present and to initiate a response that limits their absorption.

TITLE: SREBP-2 regulates gut peptide secretion through intestinal bitter taste receptor signaling in mice

AUTHOR CONTACT:
Timothy F. Osborne
University of California at Irvine, Irvine, California, USA.
Phone: (949) 824-2979; Fax: (949) 824-8551; E-mail: tfosborn@uci.edu.

MEDIA CONTACT:
Jennifer Fitzenberger
Assistant Director of Media Relations
University of California at Irvine, Irvine, California, USA.
Phone: (949) 824-3969; E-mail: jfitzen@uci.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36461

A team of researchers at Vanderbilt University, Nashville, has developed a new microscopy approach that enabled them to image, in real time, the flow of blood in mouse pancreatic islets of Langerhans.

The pancreatic islets of Langerhans have a central role in regulating the amount of glucose in the blood. Beta cells are found in the center of the islets and produce insulin, which decreases levels of glucose in the blood. They are surrounded by non-beta cells, which produce a number of other hormones, including glucagon, which increases levels of glucose in the blood. The team of researchers, led by David Piston and Alvin Powers, was able to reconstruct the in vivo 3D architecture of mouse islets and observe real-time blood flow. Two main blood-flow patterns were observed: inner-to outer, in which blood first contacted the beta-cells and then the non-beta cells, and top-to-bottom, in which blood moved from one side of the islet to the other regardless of cell type. These data have important implications for our understanding of how blood glucose levels are regulated by the cells in the pancreatic islets of Langerhans. In addition, the authors hope that this approach can be used to study blood flow in the other organs.

TITLE: Real-time, multidimensional in vivo imaging to investigate blood flow in mouse pancreatic islets

AUTHOR CONTACT:
David W. Piston
Vanderbilt University, Nashville, Tennessee, USA.
Phone: (615) 322-7004; Fax: (615) 343-0172; E-mail: al.powers@vanderbilt.edu.

Alvin C. Powers
Vanderbilt University, Nashville, Tennessee, USA.
Phone: (615) 322-7030; Fax: (615) 322-7236; E-mail: dave.piston@vanderbilt.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36209

The most common disease caused by excessive bone destruction is osteoporosis. However, regional bone loss is observed in several inflammatory conditions, including cherubism and rheumatoid arthritis. Laurie Glimcher and colleagues, at Harvard School of Public Health, Boston, have now provided new insight into the molecular control of bone degradation in mice during growth and disease, thereby uncovering a potential new therapeutic target for these diseases.

In the study, mice in which expression of the protein NFATc1 was eliminated at 10 days old developed osteopetrosis (a condition in which the bones are harder and denser than normal). This was associated with a decrease in the number of cells that destroy bone (osteoclasts). Further analysis revealed that NFATc1 regulated expression of numerous genes required for osteoclast generation. Additional experiments showed that elimination of NFATc1 in a mouse model of cherubism prevented bone loss, although it did not lessen the associated inflammation. The authors therefore conclude that NFATc1 is necessary for generating osteoclasts in growing and adult mice and might be a new therapeutic target for bone loss associated with inflammatory conditions such as cherubism.

TITLE: NFATc1 in mice represses osteoprotegrin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism

AUTHOR CONTACT:
Laurie H. Glimcher
Harvard School of Public Health, Boston, Massachusetts, USA.
Phone: (617) 432-0622; Fax: (617) 432-0084; E-mail: lglimche@hsph.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35711

Muscles are made of two different types of fibers: fast-twitch fibers, which contract quickly and powerfully, tire easily, and are suited to physical exercise such as weight lifting and sprinting; and slow-twitch fibers, which can contract for long periods of time, generate less power, and are suited to endurance events. The relative amount of each type of fiber in a muscle can change over time, allowing a muscle to adapt to changing physical demands. New insight into the molecules that control the relative amount of slow- and fast-twitch fibers in the muscles of mice has now been provided by a team of researchers at the University of Heidelberg, Germany, and the University of Texas Southwestern Medical Center, Dallas.

The researchers, led by Norbert Frey and Eric Olson, found that mice lacking the protein calsarcin-2, which is expressed exclusively by fast-twitch muscle, have substantially reduced body weight, reduced amounts of fast-twitch muscle, and increased ability to run long distances. Consistent with the improved performance in distance running, muscles of the calsarcin-2–deficient mice showed a switch toward slow-twitch fibers. Further analysis revealed a molecular mechanism for this change in the fiber-type composition of the muscles: increased activity of the calcineurin/NFAT signaling pathway, which is known to promote the formation of slow-twitch fibers. The authors therefore conclude that calsarcin-2 modulates mouse exercise performance by dampening calcineurin/NFAT signaling and thereby reducing the formation of slow-twitch muscle fibers.

TITLE: Calsarcin-2 deficiency increases exercise capacity in mice through calcineurin/NFAT activation

AUTHOR CONTACT:
Norbert Frey
University of Heidelberg, Heidelberg, Germany.
Phone: 49-6221-566877; Fax: 49-6221-564866; E-mail: norbert.frey@med.uni-heidelberg.de.

Eric N. Olson
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-1187; Fax: (214) 648-1196; E-mail: eric.olson@utsouthwestern.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36277

Immune cells known as Tregs are regulatory cells that dampen immune responses and prevent the immune system attacking the body's own tissues. It has been suggested that it might be possible to generate Tregs specifically to dampen immune responses that cause rejection of transplanted organs from donors not genetically identical to the transplant recipient. Mouse Tregs able to suppress rejection of hearts transplanted between genetically disparate donors and recipients have now been generated by Robert Lechler and colleagues, at King's College London, United Kingdom.

Tregs that directly recognized one of the main targets on the heart transplant of the destructive immune response were obtained from the intended recipient mice. These cells were then engineered so that they also indirectly recognized this target. When infused into the recipient mice, Tregs able to both directly and indirectly recognize the main target of the destructive immune response were better at preventing rejection of heart grafts than Tregs able to only directly recognize this target. The authors therefore suggest that it might be possible to engineer Tregs to be clinically useful in transplantation settings.

TITLE: Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice

AUTHOR CONTACT:
Robert Lechler
King's College London, London, United Kingdom.
Phone: 44-207-8486980; Fax: 44-207-1887675; Email: robert.lechler@kcl.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33185

Beta-cells in the pancreatic islets of Langerhans are dysfunctional in individuals with diabetes, and the molecules that control their growth and function are therefore potential therapeutic targets. While determining the role of the protein Akt1 in regulating the growth and function of mouse pancreatic beta-cells, Mario Pende and colleagues, at INSERM U845, France, generated data that might have more of an impact on anticancer therapy.

In the study, although mice engineered to overexpress a constitutively active form of Akt1 in their pancreatic beta-cells showed improved beta-cell function (because the cells were enlarged), a substantial number of the mice developed insulinomas (a rare form of pancreatic cancer) later in life and died. Further analysis revealed that the signaling protein S6K1 was required for constitutively activated Akt to cause insulinoma formation but not required for it to increase pancreatic beta-cell size. These data have implications for the development of strategies to modify pancreatic beta-cell size and function while minimizing cancer risks as well as suggesting that S6K1 might be a useful therapeutic target for individuals with some forms of cancer.

TITLE: Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation

AUTHOR CONTACT:
Mario Pende
INSERM U845, Paris, France.
Phone: 33-1-40-61-53-15; Fax: 33-1-43-06-04-43; Email: mario.pende@inserm.fr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35237