JCI table of contents: December 1, 2005
Battle of the bulge: Why losing weight is easier than keeping it off for good
You've successfully dropped those extra pounds only to discover that they creep back on again. Columbia University researchers may have now worked out why. In a study appearing in the December 1 issue of the Journal of Clinical Investigation, Michael Rosenbaum and colleagues from Columbia University College of Physicians and Surgeons show that body weight is regulated by coordinate metabolic, neuroendocrine, and autonomic systems that act to actually restore fat mass in individuals attempting to maintain their slim new figure. The authors suggest that our bodies interpret the weight-reduced state as one of relative deficiency in the hormone leptin. To test their hypothesis, the authors administered "replacement" doses of leptin to lean individuals that had recently lost weight as well as to obese individuals. The authors found that most of the metabolic, neuroendocrine, and autonomic changes that oppose the maintenance of a reduced body weight were actually reversed once circulating levels of leptin were restored to levels that were present prior to weight loss. These mechanisms lie at the center of why more than 85% of obese individuals that have lost weight eventually relapse.
These findings suggest that therapeutics directed at the leptin signaling pathway may, pending longer studies, assist in the maintenance of reduced body weight.
TITLE: Low dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight
Columbia University College of Physicians and Surgeons, New York, New York, USA
Phone: 212-305-9949; Fax: 212-851-5306; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=25977
The heat is on: why some cholesterol-lowering drugs cause hot flashes
In a study appearing in the December 1 issue of the Journal of Clinical Investigation, Stefan Offermanns and colleagues from the University of Heidelberg use various mouse models to show why the cholesterol-lowering agent nicotinic acid also commonly causes flushing or "hot flashes" that, although harmless, often prompts patients to discontinue therapy. The authors found that activation of the nicotinic acid receptor GPR109A by nicotinic acid can produce different responses dependent on the location of this receptor in the body.
The authors found that when nicotinic acid activates GPR109A expressed on the surface of fat cells it induces a lowering of lipid levels. However nicotinic acid–induced activation of GPR109A expressed on immune cells in the skin prompts the conversion of arachidonic acid to prostaglandins that cause blood vessels near the skin surface to dilate, resulting in the characteristic flushing response. In an accompanying commentary Nicholas Pike writes, "this elegant study…supports the hypothesis that immune cells in the skin are the most likely source of arachidonic acid and prostaglandins." Furthermore, this study should help researchers develop therapeutics that can achieve the same beneficial cholesterol-lowering effects of nicotinic acid, but without the marked flushing response.
TITLE: GPR109A (PUMA-G/HM74A) mediates nicotinic acid–induced flushing
University of Heidelberg, Heidelberg, Germany
Phone: +49-6221-548246; Fax: +49-6221-548549; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=23626
TITLE: Flushing out the role of GPR109A (HM74A) in the clinical efficacy of nicotinic acid
Nicholas B. Pike
GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom
Phone: 44-01438-764178; Fax: 44-01438-763232; E-mail: Nick.B.Pike@gsk.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=27160
Age and sex effect ghrelin's role in diet–induced obesity
Two studies appearing in the December 1 issue of the Journal of Clinical Investigation investigate the role of the appetite-stimulating peptide ghrelin in the regulation of food intake and the maintenance of body weight. Mark Sleeman and colleagues from Regeneron Pharmaceuticals Inc., show that male ghrelin-deficient mice exposed to a high-fat diet shortly after weaning are resistant to diet-induced obesity. This data complements that presented in the same issue of the Journal by Joel Elmquist and colleagues from Beth Israel Deaconess Medical Center who demonstrate a similar resistance to high-fat diet–induced obesity in mice that lack the ghrelin receptor GHSR. Together the 2 reports emphasize: (i) the role of ghrelin in how mice adapt metabolically to nutrient availability; (ii) that the age at which the animal is exposed to a high-fat diet plays a factor in the development of obesity; and (iii) the existence of a gender difference in body weight homeostasis in response to GSHR deficiency.
Sleeman and colleagues suggest that during the early post-weaning period there may be an interaction of the ghrelin signaling system with neuronal circuitry in the hypothalamus that controls food intake, and that the lack of ghrelin in these mice allows them to be resistant to high-fat diet–induced obesity. However, as the animals grow older, compensatory pathways in the brain may develop to adjust for the loss of ghrelin's effect on food intake, thus making these animals susceptible to obesity as they age. If these effects are reproduced in humans, they may suggest that children exposed to a high-fat diet might benefit from treatment with therapeutics that block ghrelin action.
In an accompanying commentary, Kevin Grove and Michael Cowley write, "it is possible that ghrelin antagonists may be useful in females eating a low-fat or high-fat diet, while they may only help males eating a high-fat diet. An important question to be answered is if ghrelin blockade were to be utilized as an anti-obesity therapy, to what age does this 'early' exposure in a mouse correspond in the timeline of human development?" These studies provide further hope that ghrelin blockade may have value in the treatment of obesity.
TITLE: Mice lacking ghrelin receptors resist the development of diet-induced obesity
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
Phone: 617-667-0845; Fax: 617-667-2927; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=26002
TITLE: Absence of ghrelin protects against early-onset diabesity
Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA
Phone: 914-345-7446; Fax: 914-347-5045; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=26003
TITLE: Is ghrelin a signal for the development of metabolic systems?
Kevin L. Grove
Oregon Health & Science University, Beaverton, Oregon, USA
Phone: 503-690-5380; Fax: 503-690-5384; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=27211
Sweet sixth sense: glucose-sensing glial cells guard against low blood sugar
In a study appearing in the December 1 issue of the Journal of Clinical Investigation, Bernard Thorens and colleagues from the University of Lausanne demonstrate that expression of the glucose transporter type 2 (GLUT2) in glial cells of the brain, but not in neuronal cells, is key to the direct sensing of low glucose levels (hypoglycemia), a life-threatening condition that is often caused by insulin and anti-hyperglycemic therapies.
Given the global prevalence of diabetes, hypoglycemia has become a clinically significant health issue. The life-saving response to hypoglycemia requires rapid sensing of decreases in glycemia. Thorens and co-workers report that glucose sensing in mice lacking GLUT2 is restored by re-expression of GLUT2 in glial cells, but not neuronal cells. In an accompanying commentary, Amira Klip writes, "perhaps the most far-reaching conclusion of this valuable study is the determination that glial cells are key elements in the direct sensing of glucose. This also proposes the participation of GLUT2 as a hypoglycemic sensor in addition to its more familiar role as a hyperglycemia detector." Glial cells comprise the supportive tissue of the brain but unlike neuronal cells they do not conduct electrical impulses. Just how these specific glial cells then connect to neurons within the brain to relay information about glucose level, which then prompts glucagon secretion, remains unknown.
TITLE: Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors
University of Lausanne, Lausanne, Switzerland
Phone: 41-21-692-39-81; Fax: 41-21-292-39-85; E-mail: Bernard.Thorens@unil.ch
View the PDF of this article at: https://www.the-jci.org/article.php?id=26309
TITLE: Desperately seeking sugar: glial cells as hypoglycemia sensors
The Hospital for Sick Children, Toronto, Ontario, Canada
Phone: 416-813-6392; Fax: 416-813-5028; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=27208
Mind over matter: brain GLP-1 balances the body's glucose levels
Glucagon-like peptide-1 (GLP-1) produced by the gut acts as a hormone, causing cells in the pancreas to make and release insulin to facilitate glucose uptake in the liver and muscle. As a result, GLP-1 has become the basis for new treatments for type 2 diabetes. Besides the gut, the other major site of GLP-1 production is the brain. In the December 1 issue of the Journal of Clinical Investigation, Remy Burcelin and colleagues from Paul Sabatier University, provide clear evidence that GLP-1 signaling in the central nervous system (CNS) in mice is also linked to the control of glucose homeostasis by inhibiting non–insulin-mediated glucose uptake by muscle as well as increasing insulin secretion from the pancreas. The authors propose from these findings that during the state of high blood sugar that follows a meal, CNS GLP-1 signaling inhibits glucose utilization in muscle and increases insulin secretion to favor glycogen storage in the liver, thereby preparing the body for the next period of fasting.
In an accompanying commentary, Randy Seeley and colleagues write, "this study is important because of the novel demonstration that central GLP-1 signaling appears to be connected to the control of blood glucose level." The GLP-1 receptor signaling system has become an important target in drug development with several novel compounds that target this receptor emerging onto the market. Therefore as Seeley et al. point out, "a major question raised by the present observations is the location of key populations of GLP-1 receptors regulating glucose uptake and insulin secretion."
TITLE: Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage
Paul Sabatier University, Toulouse, France
Phone: 33-461-32-34-93; Fax: 33-462-17-09-05E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=25764
TITLE: New ways in which GLP-1 can regulate glucose homeostasis
Randy J. Seeley
Genome Research Institute, University of Cincinnati, Cincinnati, Ohio, USA
Phone: 513-558-6664; Fax: 513-558-8990; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=27207
Antigen sends chronic myeloid leukemia into remission
Differences in minor histocompatibility antigens (mHAgs) are important for both host rejection of grafts as well as the curative graft-versus-leukemia (GVL) effect. In the December 1 issue of the Journal of Clinical Investigation Harry Dolstra and colleagues from Radboud University describe a new mHAg: lymphoid-restricted histocompatibility antigen 1 (LRH-1). Following hematopoietic stem cell transplantation in a patient with chronic myeloid leukemia, the authors observed a massive rise in the number of LRH-1–specific T cells that coincided with remission of leukemic disease.
The authors found that, in the transplant recipient, the P2X5 gene (which codes for LRH-1) contained a single nucleotide deletion, resulting in a frame-shift. In an accompanying commentary, Eric Spierings and Els Goulmy write, "generation of an mHAg via nucleotide insertion/deletion has not been described before and presents interesting opportunities to further exploit the P2X5 gene-product as a source for mHAgs to be used for immunotherapy." This result represents another example of an mHAg-mediated GVL response, thereby expanding the number of patients eligible for mHAg-based immunotherapy following hematopoietic stem cell transplantation.
TITLE: A frameshift polymorphism in P2X5 elicits an allogeneic cytotoxic T lymphocyte response associated with remission of chronic myeloid leukemia
Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Phone: 31-24-3619753; Fax: 31-24-3568408; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24832
TITLE: Expanding the immunotherapeutic potential of minor histocompatibility antigens
Leiden University Medical Center, Leiden, The Netherlands
Phone: 31-71-5261966; Fax: 31-71-5216751; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=27094
New microarray technology predicts disease activity in lupus
In the December 1 issue of the Journal of Clinical Investigation, Chandra Mohan and colleagues from UT Southwestern Medical Center used new proteome microarray technology to study the autoantibody profile in lupus nephritis and identify those autoantibodies that best correlate with disease activity. The authors identified several antigens that are targeted by autoantibodies in mouse and human lupus sera, which had not been previously identified. The authors reveal that these autoantibodies tend to cluster in groups that are associated with the degree of disease severity.
This technology appears to show promise as a powerful analytical tool for uncovering autoantibody-disease associations and for distinguishing patients at high risk for end-organ disease.
TITLE: Identification of autoantibody clusters that best predict lupus disease activity using glomerular proteome arrays
University of Texas Southwestern Medical Center, Dallas, Texas, USA
Phone: 214-648-9675; Fax: 214-648-7995; E-mail: Chandra.firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=23587
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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