Decreased glucose tolerance and plasma adiponectin:resistin ratio in a mouse model of post-traumatic stress disorder.

AIMS/HYPOTHESIS: Obesity and type 2 diabetes are among the most serious health pathologies worldwide. Stress has been proposed as a factor contributing to the development of these health risk factors; however, the underlying mechanisms that link stress to obesity and diabetes need to be further clarified. Here, we study in mice how chronic stress affects dietary consumption and how that relationship contributes to obesity and diabetes. METHODS: C57BL/6J mice were subjected to chronic variable stress (CVS) for 15 days and subsequently fed with a standard chow or high-fat diet. Food intake, body weight, respiratory quotient, energy expenditure and spontaneous physical activity were measured with a customised calorimetric system and body composition was measured with nuclear magnetic resonance. A glucose tolerance test was also applied and blood glucose levels were measured with a glucometer. Plasma levels of adiponectin and resistin were measured using Lincoplex kits. RESULTS: Mice under CVS and fed with a high-fat diet showed impaired glucose tolerance associated with low plasma adiponectin:resistin ratios. CONCLUSIONS/INTERPRETATION: This study demonstrates, in a novel mouse model, how post-traumatic stress disorder enhances vulnerability for impaired glucose metabolism in an energy-rich environment and proposes a potential adipokine-based mechanism.

Ghrelin in the regulation of body weight and metabolism.

Ghrelin, a peptide hormone predominantly produced by the stomach, was isolated as the endogenous ligand for the growth hormone secretagogue receptor. Ghrelin is a potent stimulator of growth hormone (GH) secretion and is the only circulatory hormone known to potently enhance feeding and weight gain and to regulate energy homeostasis following central and systemic administration. Therapeutic intervention with ghrelin in catabolic situations may induce a combination of enhanced food intake, increased gastric emptying and nutrient storage, coupled with an increase in GH thereby linking nutrient partitioning with growth and repair processes. These qualities have fostered the idea that ghrelin-based compounds may have therapeutic utility in treating malnutrition and wasting induced by various sub-acute and chronic disorders. Conversely, compounds that inhibit ghrelin action may be useful for the prevention or treatment of metabolic syndrome components such as obesity, impaired lipid metabolism or insulin resistance. In recent years, the effects of ghrelin on glucose homeostasis, memory function and gastrointestinal motility have attracted considerable amount of attention and revealed novel therapeutic targets in treating a wide range of pathologic conditions. Furthermore, discovery of ghrelin O-acyltransferase has also opened new research opportunities that could lead to major understanding of ghrelin physiology. This review summarizes the current knowledge on ghrelin synthesis, secretion, mechanism of action and biological functions with an additional focus on potential for ghrelin-based pharmacotherapies.

Effect of central administration of QRFP(26) peptide on energy balance and characterization of a second QRFP receptor in rat.

The recently identified neuropeptide QRFP(26) is predominantly expressed in the hypothalamus and was suggested to play a role in the regulation of food intake following the observation of an acute orexigenic effect after central administration in mice. QRFP(26) exerts its effect via GPR103 and a newly identified receptor in mouse. The aim of our study was (a) to investigate the distribution of QRFP(26) and a newly discovered QRFP receptor mRNA in rat and (b) to further characterize the effects of central administration of QRFP(26) on energy balance in rats. QRFP(26) mRNA was detected in the retrochiasmatic nucleus, periventricular nucleus, arcuate nucleus and restricted areas of the lateral nucleus of the hypothalamus. We found an additional receptor with high homology for GPR103 in rat. This receptor increases inositol triphosphate production in transfected cells in presence of QRFP(26) and its mRNA was particularly enriched in ventral and posterior thalamic groups, anterior hypothalamus and medulla. When QRFP(26) (10 microg and 50 microg) was administered centrally before the start of the light phase both doses increased food intake for 2 h after injection without reaching statistical significance. QRFP(26) caused no changes in locomotor activity or energy expenditure. In summary, central QRFP(26) injection causes slight and transient hyperphagia in rats without changing any other energy balance parameters after 24 h. We conclude that QRFP(26) has limited impact on the central regulation of energy balance in rats and that its essential function remains to be clarified.

PYY3-36 as an anti-obesity drug target.

The neuropeptide Y (NPY)/peptide YY (PYY) system has been implicated in the physiology of obesity for several decades. More recently ignited enormous interest in PYY3-36, an endogenous Y2-receptor agonist, as a promising anti-obesity compound. Despite this interest, there have been remarkably few subsequent reports reproducing or extending the initial findings, while at the same time studies finding no anti-obesity effects have surfaced. Out of 41 different rodent studies conducted (in 16 independent labs worldwide), 33 (83%) were unable to reproduce the reported effects and obtained no change or sometimes increased food intake, despite use of the same experimental conditions (i.e. adaptation protocols, routes of drug administration and doses, rodent strains, diets, drug vendors, light cycles, room temperatures). Among studies by authors in the original study, procedural caveats are reported under which positive effects may be obtained. Currently, data speak against a sustained decrease in food intake, body fat, or body weight gain following PYY3-36 administration and make the previously suggested role of the hypothalamic melanocortin system unlikely as is the existence of PYY deficiency in human obesity. We review the studies that are in the public domain which support or challenge PYY3-36 as a potential anti-obesity target.

Amphetamine releases GABA in striatum of the freely moving rat: involvement of calcium and high affinity transporter mechanisms.

Using microdialysis the effect was investigated of amphetamine (AMPH) infusions into the striatum on the release of GABA in the freely moving rat. AMPH (5, 10 and 20 microg/microl), infused through a microdialysis probe at the rate of 2.5 microl/min, produced a dose-related increase in extracellular concentrations of GABA. At the highest dose (20 microg/microl), AMPH increased GABA from 0.08 +/- 0.01 to 0.67 +/- 0.14 microM. Increases in extracellular GABA produced by AMPH were both calcium-dependent and high affinity GABA transporter-mediated. A medium free of calcium reduced the increase of extracellular GABA produced by AMPH by 37%. Nipecotic acid (2, 4 and 8 mM), a specific GABA re-uptake blocker, significantly attenuated increases in extracellular GABA, but not GLU, produced by AMPH (20 microg/microl). This study is the first in vivo evidence showing the release of GABA produced by AMPH through a high affinity transporter mechanism.