JCI online early table of contents: Feb. 1, 2010
EDITOR'S PICK: Preventing pancreatic islet loss after transplantation Although transplantation of pancreatic islets is an attractive way to treat type 1 diabetes, early islet loss soon after transplantation has limited its clinical use. By studying islet transplantation in a mouse model of diabetes, a team of researchers, at the RIKEN Research Center for Allergy and Immunology, Japan, and Fukuoka University, Japan, has now identified a potential new set of targets to improve the efficiency of pancreatic islet transplantation.
Previous studies have identified an immune mechanism essential for early loss of transplanted islets: immune cells expressing the proteins Gr-1 and CD11b produce the soluble molecule IFN-gamma in a process that is dependent on immune cells known as NKT cells. The team, led by Masaru Taniguchi and Yohichi Yasunami, found that the protein HMGB1 plays a crucial role in the initial events of early loss of transplanted islets in the mouse model of diabetes. Of potential clinical significance, treatment with an antibody targeting HMGB1 prevented early pancreatic islet loss and inhibited IFN-gamma production by NKT cells and Gr-1+CD11b+ cells. Furthermore, mice lacking either of the two proteins to which HMGB1 binds failed to exhibit early pancreatic islet loss. Additional analysis identified the molecular pathway linking HMGB1 to NKT cell activation and subsequent NKT cell–dependent IFN-gamma production by Gr-1+CD11b+ cells, and targeting some of these molecules prevented early pancreatic islet loss. These data provide several potential drug targets for improving the efficiency of pancreatic islet transplantation in humans.
TITLE: High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice
RIKEN Research Center for Allergy and Immunology, Yokohama, Japan.
Phone: 81-45-503-7001; Fax: 81-45-503-7003; E-mail: firstname.lastname@example.org.
Faculty of Medicine Fukuoka University, Fukuoka, Japan.
Phone: 81-92-801-1011 ext. 3630; Fax: 81-92-801-1019; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/41360?key=82f6533c5783a48c4c6c
METABOLIC DISEASE: Making macrophages protect against effects of obesity
It is well known that diet-induced obesity increases dramatically a person's risk of developing type 2 diabetes. One reason underlying this susceptibility is that diet-induced obesity triggers the accumulation of inflammatory immune cells known as macrophages in fat tissue known as white adipose tissue (WAT). A team of researchers, led by Robert Farese Jr. and Suneil Koliwad, at the Gladstone Institute of Cardiovascular Disease, San Francisco, has now determined that engineering macrophages to store increased amounts of triacylglycerol (the main constituent of vegetable oil and animal fats) is sufficient to protect mice from diet-induced inflammatory macrophage activation, macrophage accumulation in WAT, and insulin resistance, a condition that preempts the onset of type 2 diabetes.
The team made macrophages store increased amounts of triacylglycerol by using mice overexpressing the protein DGAT1, which is crucial for triaclyglycerol synthesis, in macrophages and fat cells. They then generated in vitro evidence to support their hypothesis that increasing DGAT1 expression in mouse macrophages increases their ability to store triacylglycerol and reduces the inflammatory and clinical consequences of diet-induced obesity. Of clinical interest, the ability of antidiabetic agents known as PPARγ agonists to suppress fat-mediated inflammatory activation of cultured macrophages was abrogated if the cells were DGAT1-deficient. The authors therefore suggest that modulating DGAT1 levels in human macrophages might be a crucial mechanism underlying the antidiabetic effects of PPARγ agonists.
TITLE: DGAT1-dependent triacylglycerol storage by macrophages protects mice from diet-induced insulin resistance and inflammation
Robert V. Farese Jr.
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
Phone: 415.734.2718; Fax: 415.355.0960; E-mail: firstname.lastname@example.org.
Suneil K. Koliwad
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
Phone: 415.734.2718; Fax: 415.355.0960; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/36066?key=c4510027933fec792002
REPRODUCTIVE BIOLOGY: Role for the protein p53 in maintaining pregnancy to term
Premature delivery accounts for 75% of early neonatal morbidity and mortality, and those babies that survive preterm birth are at increased risk of serious long-term health complications. New research, performed by Sudhansu K. Dey and colleagues, at the University of Cincinnati College of Medicine, Ohio, indicates that expression of the protein p53, which is best known as a tumor suppressor that is mutated in many types of cancer, in the uterus is important for female mice to maintain a pregnancy to term.
The researchers generated mice lacking p53 in the uterus only and found that they had an increased incidence of preterm birth. Additional evidence, including the observation that oral administration of the drug celecoxib, which is a selective inhibitor of the protein COX2, prevented preterm birth in mice lacking p53 only in the uterus, led the authors to conclude that lack of p53 in the uterus induces preterm birth through a COX2/PGF synthase/PGF2-alpha pathway. The authors go on to suggest that their data may provide a connection between two previously reported observations: first, that women aged 35 or older are at higher risk of premature birth; and second, that p53 activity diminishes in mice as they age.
TITLE: Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice
Sudhansu K. Dey
University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Phone: (513) 803-1158; Fax: (513) 803-1160; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/40051?key=134a6ae741eb32d948e4
MUSCLE BIOLOGY: Peak muscle performance requires two forms of nNOS protein
The protein nNOS-mu, which is just one form of the nNOS protein, is essential for skeletal muscle health, and signaling via nNOS-mu is commonly reduced in neuromuscular disease. Now, Justin Percival and colleagues, at the University of Washington, Seattle, have identified a crucial role for the nNOS-beta form of nNOS in mouse skeletal muscle, where it enables skeletal muscle to maintain force production during and after exercise.
In the study, mouse muscles lacking both nNOS-beta and nNOS-mu were found to be smaller in mass, to be intrinsically weaker, to be more susceptible to fatigue, and to exhibit more marked postexercise weakness than mouse muscles lacking only nNOS-mu. The specific function of nNOS-beta was determined to be regulation of skeletal muscle structural and functional integrity. By contrast, previous data have indicated that nNOS-mu helps match blood supply with the metabolic demands of active muscle. These distinct roles for nNOS-beta and nNOS-mu are likely a result of the fact that the authors found the two proteins at distinct locations within skeletal muscle cells; the former was localized to the Golgi apparatus and the latter to the sarcolemma. These data indicate that nNOS proteins are critical regulators of skeletal muscle exercise performance.
TITLE: Golgi and sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue and vasoconstriction in exercising mouse skeletal muscle
Justin M. Percival
University of Washington, Seattle, Washington, USA.
Phone: 206.543.9094; Fax: 206.685.0619; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/40736?key=26cf10faaf056e879fa5
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