Regulation of food intake by oleoylethanolamide.

Oleoylethanolamide (OEA), the naturally occurring amide of ethanolamine and oleic acid, is an endogenous lipid that modulates feeding, body weight and lipid metabolism by binding with high affinity to the ligand-activated transcription factor, peroxisome proliferator-activated receptor-alpha (PPAR-alpha). In the present article, we describe the biochemical pathways responsible for the initiation and termination of OEA signaling, and outline the pharmacological properties of this compound in relation to its ability to activate PPAR-alpha. Finally, we discuss the possible role of OEA as a peripheral satiety hormone.

Induction of oxidative stress by glutathione depletion causes severe hypertension in normal rats.

Several recent studies have shown that certain forms of genetic or acquired hypertension are associated with oxidative stress and that animals with those types of hypertension respond favorably to antioxidant therapy. We hypothesize that oxidative stress may cause hypertension via (among other mechanisms) enhanced oxidation and inactivation of nitric oxide (NO). To test this hypothesis, Sprague-Dawley rats were subjected to oxidative stress by glutathione (GSH) depletion by means of the GSH synthase inhibitor buthionine sulfoximine (BSO, 30 mmol/L in drinking water) for 2 weeks. The control group was given drug-free drinking water. In parallel experiments, subgroups of animals were provided vitamin E-fortified chow and vitamin C-supplemented drinking water. The BSO-treated group showed a 3-fold decrease in tissue GSH content, a marked elevation in blood pressure, and a significant reduction in the urinary excretion of the NO metabolite nitrate plus nitrite, which suggests depressed NO availability. These characteristics were associated with a significant accumulation in various tissues of nitrotyrosine, which is the footprint of NO inactivation by reactive oxygen species. Administration of vitamin E plus vitamin C ameliorated hypertension, improved urinary nitrate-plus-nitrite excretion, and mitigated nitrotyrosine accumulation (despite GSH depletion) in the BSO-treated animals but had no effect in the control group. In conclusion, GSH depletion resulted in perturbation of the NO system and severe hypertension in normal animals. The effects of BSO were mitigated by concomitant antioxidant therapy despite GSH depletion, which supports the notion that oxidative stress was involved in the pathogenesis of hypertension in this model.

Effects of experimental hemosiderosis on intestinal morphology, permeability, and tissue iron content.

Effects of iron overload on intestinal function and structure are unknown and were, therefore, investigated. Sprague-Dawley rats were randomized into an iron-overloaded group, which received a single subcutaneous injection of 1.2 g/kg elemental iron-dextran complex, and placebo-treated pair-fed controls. Animals were studied after a 10-month observation period. Intestinal permeability was assessed by measuring the urinary excretion of lactulose, rhamnose, and mannitol after oral administration. In addition, tissue nonheme iron content was measured, and histologic examination and morphometric measurements were carried out. The chronic iron-overloaded group showed a significant increase in intestine tissue iron content and stainable iron in the submucosa and muscularis propria and adipose tissue of the small intestine and lamina propria and muscularis mucosa of the large intestine. There was a significant decrease in the crypt depths without discernible change in the intestine permeability to any of the markers used. In addition, the iron-overloaded animals showed a significant number of iron-laden cells, which primarily consisted of macrophages, fibroblasts, myocytes, and adipocytes. In contrast, no iron-laden cells were present in tissues obtained from the normal control group. Thus, chronic experimental iron overload in rats leads to significant morphologic, but no permeability, alterations of the alimentary tract.

Radiodetoxified endotoxin-induced tolerance alters monocyte but not neutrophil CD11b and CD18 expression in response to lipopolysaccharide.

OBJECTIVES: To test the hypothesis that pretreatment with radiodetoxified endotoxin (RDE) may mitigate the deleterious effects of subsequent infection, in part by modifying leukocyte adhesion receptor expression, and to investigate the cellular mechanisms of endotoxin tolerance induced by RDE. DESIGN: To assess the effect of RDE pretreatment on mortality from bacterial peritonitis, rats were implanted with an intraperitoneal, barium-fecal inoculum at intervals of 0, 1, 3, and 5 days after RDE injection. Experiments were then conducted to test the effect on leukocyte adhesion receptor expression. Two groups of mice received saline solution, and one group, RDE. After 72 hours, one group received saline solution (saline/saline group), the others, lipopolysaccharide (LPS) (saline/LPS and RDE/LPS groups). Peripheral leukocytes were obtained 1 hour after injection and were analyzed for CD11b and CD18 expression by flow cytometry. SETTING: Laboratory animal study. RESULTS: Survival rates were not improved in rats that were pretreated with RDE 0 and 24 hours before inoculum (0% and 7%, respectively). In rats that were pretreated 72 hours and 120 hours before inoculum, 47% (P < .01) and 60% (P < .01) survived, respectively. CD18 expression on polymorphonuclear leukocytes increased twofold in the RDE/LPS (mean +/- SEM, 300.3 +/- 32.9) and the saline/LPS (mean +/- SEM, 360.4 +/- 59.9) groups compared with controls (mean +/- SEM, 176.4 +/- 18.9) (P < .05). CD11b expression on polymorphonuclear leukocytes increased threefold in the RDE/LPS (mean +/- SEM, 91.3 +/- 8.1) and the saline/LPS (mean +/- SEM, 89.8 +/- 11.4) groups compared with controls (mean +/- SEM, 32.1 +/- 1.8) (P < .05). CD18 expression on monocytes decreased in the saline/LPS group (mean +/- SEM, 134.2 +/- 14.2) and was unchanged in the RDE/LPS group (mean +/- SEM, 200.2 +/- 17.2) compared with controls (mean +/- SEM, 217.6 +/- 16.5) (P < .05). CD11b expression on monocytes decreased in the saline/LPS group (mean +/- SEM, 25.8 +/- 2.2) and was unchanged in the RDE/LPS group (mean +/- SEM, 36.4 +/- 0.9) compared with controls (mean +/- SEM, 39.7 +/- 3.9) (P < .05). CONCLUSIONS: Radiodetoxified endotoxin reduces mortality rates from bacterial peritonitis when given at least 72 hours prior to a bacterial inoculum. Tolerance to subsequent LPS challenge is associated with an abrogation of the reduced peripheral monocyte CD11b and CD18 expression observed in native LPS-stimulated mice but is not associated with changes in polymorphonuclear leukocyte CD11b and CD18 expression. The mechanism of the observed RDE-induced monocyte hyporesponsiveness to LPS and its possible protective effect is uncertain and requires further investigation.

The pituitary-gonadal axis in experimental nephrotic syndrome in male rats.

Basal and luteinizing releasing hormone-stimulated gonadotropin secretion were studied in male rats made nephrotic with puromycin, and in pair-fed and normal control animals. In addition, plasma concentrations of testosterone, androstenedione, estradiol, and estrone were measured in the three groups of animals. Urinary testosterone concentrations were also measured in the three experimental groups. The data showed that basal luteinizing hormone concentration was significantly elevated in the nephrotic group compared with the pair-fed and normal control groups. Gonadotropin response to luteinizing releasing hormone stimulation was not significantly different in the three groups, suggesting an intact hypothalamic-pituitary axis in nephrotic syndrome. Urinary testosterone concentration in the nephrotic animals was significantly higher than in the pair-fed and normal control groups. Plasma testosterone, androstenedione, estradiol, and estrone concentrations were significantly lower in the nephrotic and pair-fed animals than in the normal control animals, indicating possibly impaired gonadal steroidogenesis in these two groups that may be related to the catabolic state of the animals. It thus appears that urinary loss of protein-bound (sex hormone binding globulin-bound) testosterone in the nephrotic syndrome leads to increased basal secretion of luteinizing hormone, presumably as a result of increased luteinizing releasing hormone secretion. This occurs to compensate for the abnormal urinary testosterone loss and is an attempt to restore plasma testosterone concentrations to normal. The higher basal plasma luteinizing hormone concentration in the nephrotic group supports this conclusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional, biochemical, and histopathologic consequences of high-dose interleukin-2 administration in rats.

A variety of side effects have been reported with the use of interleukin-2 alone or in combination with lymphokine-activated killer cells in patients with disseminated neoplasms. The present study was undertaken to determine the effects of high-dose interleukin-2 administration in normal rats. Sprague-Dawley rats were treated with intravenous recombinant interleukin-2 (900,000 IU/kg/day) for 9 consecutive days. Animals were placed in individual metabolic cages, and arterial blood pressure, food intake, body weight, and urine output were monitored. On day 10, animals were killed by exsanguination, various tissues were harvested, and a variety of hematologic and chemical assays were performed. The results were compared with those of placebo-injected normal control and pair-fed groups. The interleukin-2-treated group exhibited anorexia, weight loss, hypotension, anemia, leukocytosis, lymphocytosis, eosinophilia, hypercalcemia, azotemia, and a marked urinary concentration defect. Histologic examination of various tissues revealed widespread infiltration with mono-nuclear cells and eosinophils in most organs, especially in the lungs and liver of interleukin-2-treated animals. Other abnormalities included severe panlobular hepatitis, hepatocellular necrosis, and thymic involution. Renal involvement was mild and consisted of focal interstitial infiltration by mononuclear cells. According to these observations, administration of high-dose interleukin-2 in normal rats results in a score of significant functional, biochemical, and histologic abnormalities.