JCI table of contents, March 9, 2006EDITOR'S PICK
Fat rats reveal why short-term overeating can lead to obesity and diabetes
Obesity is due to a mismatch between the number of calories we consume and the amount of physical activity we undertake. In the brain, a region called the hypothalamus control ours eating behavior through its metabolism of fat molecules called fatty acids. Interestingly, eating too much in the short-term can result in a severe drop in the ability of the body (and brain) to be satisfied by fat and to control blood sugar levels. In a study appearing online on March 9 in advance of print publication in the April issue of the Journal of Clinical Investigation, Luciano Rossetti and colleagues at Albert Einstein College of Medicine in New York report that inhibiting an enzyme in the liver called carnitine palmitoyltransferase-1 (CPT1A), which is involved in metabolizing fatty acids, inhibits feeding. The researchers placed normal rats on a lard-based diet, which stimulated the animals to voluntarily overeat and gain weight. When the researchers inhibited CPT1A by delivering special molecules called "ribozymes" into the brain of the rats, the animals ate dramatically less. The treatment also improved the blood sugar levels of these animals, who suffered from a common metabolic impairment known as insulin resistance, in which the body is unable to respond properly to insulin. The authors report that this animal model of diet-induced obesity and insulin resistance displayed defective adaptation to an increase in fat availability coupled with a severe impairment in the ability of the brain to sense fat intake. Further studies will be required to establish the critical role of this biochemical pathway in nutrient sensing in other animal models and, critically, in humans.
TITLE: Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats
Albert Einstein College of Medicine, New York, New York, USA
Phone: (718) 430-4118; Fax: (718) 430-8557; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=26640
How sweet it is: scientists find cellular link between insulin resistance and heart disease
Insulin resistance (IR) is a metabolic disorder in which the body does not respond to the insulin produced by the pancreas, typically resulting in elevated blood sugar levels and diabetes. Importantly, individuals with diabetes also have a significantly higher risk of developing cardiovascular disease (CVD), even after accounting for risk factors such as elevated cholesterol levels and high blood pressure. Now, in a study appearing online on March 9 in advance of print publication in the April issue of the Journal of Clinical Investigation, Michael Brownlee and colleagues at Albert Einstein College of Medicine in New York show a link between the metabolism of lipids called free fatty acids (FFAs) and a tissue damaging oxidant called "superoxide." The researchers measured the effects of FFA metabolism in cells from the aortas of cows, when the cells were treated with a high sugar solution to mimic the events that occur in the blood vessels during insulin resistance and diabetes. The authors found that the cells metabolized FFAs, which led to increased production of superoxide and the activation of a variety of inflammatory signals previously implicated in high–blood-sugar–induced vascular damage. In addition, the authors also found that two important antiatherogenic enzymes, prostacyclin synthase and eNOS, were inactivated, suggesting that insulin resistance and high blood sugar can directly damage the cells of blood vessels, contributing to heart disease. The researchers also examined mouse and rat animal models of insulin resistance, and found that inactivation of prostacyclin synthase and eNOS was prevented by reduction of superoxide levels. The study results suggest that these experiments have identified a novel mechanism that contributes to the accelerated cardiovascular disease risk occurring in people with insulin resistance.
TITLE: Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation
Albert Einstein College of Medicine, Bronx, New York, USA
Phone: (718) 430-3636; Fax: (718) 430-8570; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=23354
Creating vitamin D-related compounds with fewer side effects for the treatment of osteoporosis and skin disorders
Vitamin D and drugs with structures similar to vitamin D, are called vitamin D receptor (VDR) ligands because they exert their actions in the body by binding to a special cell protein called the vitamin D receptor. Importantly, VDR ligands are therapeutic agents for the treatment of psoriasis, osteoporosis, and show immense therapeutic potential for autoimmune diseases and cancers of skin, prostate, colon, and breast as well as leukemia. However, the major side effect of VDR ligands is hypercalcemia, which develops due to adverse effects in the intestine. In a study appearing online on March 9 in advance of print publication in the April issue of the Journal of Clinical Investigation, researchers Sunil Nagpal and colleagues at Eli Lilly and Company describe new drugs called "tissue-selective VDR modulators" or VDRMs), which have high activity in skin and bone, with poor activity in the intestine, therefore reducing the negative side effects of these compounds. The researcher designed two compounds called LY2108491 and LY2109866, and found that mice treated with these compounds developed increased thickness of the epidermal layer of their skin, a model which suggests that the compounds will inhibit psoriasis-related symptoms in humans. Using isolated human cells in laboratory dishes, the authors also showed that these compounds have potent action in other target cells such as keratinocytes of the skin, osteoblasts of bone, and blood cells. Further work on these and related compounds may lead to the development of potent treatments for cancers, psoriasis, and osteoporosis that have fewer unwanted side effects.
TITLE: Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators
Eli Lilly and Company, Indianapolis, Indiana, USA
Phone: (484) 865-5627; Fax: (484) 865-9389; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=25901
Human gene mutation causes kidney stones and kidney failure
Mutations in a human gene known as Claudin16 are responsible for certain causes of kidney failure and kidney stones, and increased urine calcium and magnesium levels. However, the precise effects that these different mutations have on claudin16 protein structure and biological action are unclear. Now, in a study appearing online on March 9 in advance of print publication in the April issue of the Journal of Clinical Investigation, Walter Hunziker and colleagues from the Institute of Molecular and Cell Biology in Singapore have identified that the majority of mutations in claudin16, which is normally located on the surface of kidney cells, cause the protein to get stuck inside the cells or get degraded by the cell's own protein-destroying machinery. The researchers created 21 synthetic DNA molecules called "plasmids" which each contained a single mutant form of the claudin16 gene sequence, and put these plasmids into kidney cells in the laboratory. The cells were able to produce the mutant claudin16 protein. The authors made an antibody that recognized claudin16 protein and used it to determine where in the cells the various mutants were localized. Incubating the cells with this antibody revealed that most of the mutants, in contrast to the normal version of claudin16, were either degraded by the cell or they became trapped in various places inside the cell and thus could not function properly. In addition, when the researchers examined the movement of calcium and magnesium in and out of the cells, they found that cells that expressed the mutant claudin16 forms of the protein had defects in trafficking calcium and magnesium. The authors report that this study is important for the potential future therapeutic interventions that claudin16 corrective therapy may provide for patients with excess calcium loss due to these genetic mutations.
TITLE: Disease-associated mutations affect intracellular traffic and paracellular Mg2+ transport function of Claudin-16
Institute of Molecular and Cell Biology, Singapore
Phone: 65-6586-9599; Fax: 65-6779-1117; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=26323
New mechanism for allergic asthma identified
In a study appearing online on March 9 in advance of print publication in the April issue of the Journal of Clinical Investigation, Gesine Hansen and colleagues at Medizinische Hochschule Hannover in Germany have identified a potentially new target for treating asthma. The researchers examined a mouse model of asthma, which develops human-like asthma symptoms including airway hyperresponsiveness (AHR), mucus production, production of proinflammatory proteins called cytokines, and increased numbers of immune cells called eosinophils and Th2 cells in the lung. The researchers injected these asthmatic mice with an antibody that stimulates the activity of an immune protein called CD137. A single injection of this "agonistic" anti-CD137 antibody was able to inhibit AHR, eosinophilic airway inflammation, and Th2 cytokine production for the complete observation period of almost 7 weeks. The lasting effects of this treatment suggest that this type of antibody therapy may be used in the future to treat the recurring symptoms of allergy in humans. Specifically, the authors suggest that strategies aimed at stimulation of CD137, which has previously been shown to induce tumor rejection, may represent a clinical target for allergic inflammatory responses and other disorders characterized by inappropriate T cell activation.
TITLE: CD137-mediated immunotherapy for allergic asthma
Hannover, Hannover, Germany
Phone: 0049-511-532-9138; Fax: 0049-511-532-9125; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=23792
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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