The effect of neonatal maternal stress on plasma levels of adrenocorticotropic hormone, corticosterone, leptin, and ghrelin in adult male rats exposed to acute heterotypic stressor.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is important for maintenance of homeostasis during stress. Recent studies have shown a connection between the HPA axis and adipose tissue. The present study investigated the effect of acute heterotypic stress on plasma levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), leptin, and ghrelin in adult male rats with respect to neonatal maternal social and physical stressors. Thirty rat mothers and sixty of their male progeny were used. Pups were divided into three groups: unstressed control (C), stressed by maternal social stressor (S), stressed by maternal social and physical stressors (SW). Levels of hormones were measured in adult male progeny following an acute swimming stress (10 min) or no stress. ELISA immunoassay was used to measured hormones. The ACTH and CORT levels were significantly increased in all groups of adult progeny after acute stress; however, CORT levels were significantly lower in both neonatally stressed groups compared to controls. After acute stress, plasma leptin levels were decreased in the C and SW groups but increased in the S group. The data suggest that long-term neonatal stressors lead to lower sensitivity of ACTH receptors in the adrenal cortex, which could be a sign of stress adaptation in adulthood. Acute stress in adult male rats changes plasma levels of leptin differently relative to social or physical neonatal stressors.

Changes in FGF21 serum concentrations and liver mRNA expression in an experimental model of complete lipodystrophy and insulin-resistant diabetes.

Patients with obesity and type 2 diabetes often display high levels of the anti-diabetic factor fibroblast growth factor-21 (FGF21), suggesting that the overproduction of FGF21 may result from increased adiposity in an attempt by white adipose tissue (WAT) to counteract insulin resistance. However, the production of FGF21 diabetes in the absence of WAT has not been examined. In this study, we investigated the effects of lipodystrophy in A-ZIP F-1 mice on FGF21 production in relation to diabetes. A-ZIP F-1 mice displayed high FGF21 plasma levels resulting from enhanced FGF21 mRNA expression in the liver. Concomitant enhancement of FGF21 receptor (FGFR1) and glucose transporter 1 (GLUT-1) mRNA expression was observed in the muscles of A-ZIP F-1 mice. Furthermore, the activation of hypothalamic NPY and AgRP mRNA expression positively correlated with plasma levels of FGF21 but not active ghrelin. Our study demonstrates that an increased FGF21 plasma level in lipodystrophic A-ZIP F-1 mice results mainly from up-regulated liver production but does not suffice to overcome the lipodystrophy-induced severe type 2-diabetes and insulin resistance in the liver linked to the augmented liver fat deposition.

Triazole GHS-R1a antagonists JMV4208 and JMV3002 attenuate food intake, body weight, and adipose tissue mass in mice.

The only peripherally released orexigenic hormone, ghrelin, plays a key role in food intake and body weight regulation. Antagonizing the ghrelin receptor, GHS-R1a, represents a promising approach for anti-obesity therapy. In our study, two novel GHS-R1a antagonists JMV4208 and JMV3002, which are trisubstituted 1,2,4-triazoles, decreased food intake in fasted lean mice in a dose-dependent manner, with ED50 values of 5.25 and 2.05 mg/kg, respectively. Both compounds were stable in mouse blood, with half-lives of 90 min (JMV4208) and 60 min (JMV3002), and disappeared from the blood 8h after administration. Fourteen days of treatment with the ghrelin antagonists (20 mg/kg twice a day) decreased food intake, body weight and adipose tissue mass in mice with diet-induced obesity (DIO). These results are likely attributable to an impact on food intake reduction and an attenuated expression of the lipogenesis-promoting enzymes (acetyl-CoA carboxylase 1 in subcutaneous fat and fatty acid synthase in subcutaneous and intraperitoneal fat). The decrease in fat mass negatively impacted circulating leptin levels. These data suggest that JMV4208 and JMV3002 could be useful therapeutic agents for the treatment of obesity.

Ghrelin agonist JMV 1843 increases food intake, body weight and expression of orexigenic neuropeptides in mice.

Ghrelin and agonists of its receptor GHS-R1a are potential substances for the treatment of cachexia. In the present study, we investigated the acute and long term effects of the GHS R1a agonist JMV 1843 (H Aib-DTrp-D-gTrp-CHO) on food intake, body weight and metabolic parameters in lean C57BL/6 male mice. Additionally, we examined stability of JMV 1843 in mouse blood serum. A single subcutaneous injection of JMV 1843 (0.01-10 mg/kg) increased food intake in fed mice in a dose-dependent manner, up to 5-times relative to the saline-treated group (ED(50)=1.94 mg/kg at 250 min). JMV 1843 was stable in mouse serum in vitro for 24 h, but was mostly eliminated from mouse blood after 2 h in vivo. Ten days of treatment with JMV 1843 (subcutaneous administration, 10 or 20 mg/kg/day) significantly increased food intake, body weight and mRNA expression of the orexigenic neuropeptide Y and agouti-related peptide in the medial basal hypothalamus and decreased the expression of uncoupling protein 1 in brown adipose tissue. Our data suggest that JMV 1843 could have possible future uses in the treatment of cachexia.

Transient anorexia, hyper-nociception and cognitive impairment in early adjuvant arthritis in rats.

OBJECTIVE: Rheumatoid arthritis (RA) is associated with enhanced pro-inflammatory cytokine levels, pain, anorexia, and cognitive changes. The enhanced production of cytokines appears before the full manifestation of the disease. So far, any experimental data on behavioral effects of early arthritis are lacking. In the present series we describe anorexia early changes in, pain hyper-sensitivity and altered cognitive behavior during the first four days of adjuvant arthritis in rats (AA), when no clinical signs are yet apparent. METHODS: AA was induced to male Lewis rats by a single injection of complete Freund's adjuvant (cFA) at the base of the tail. Plasma leptin and ghrelin were measured using specific RIA methods. Gene expressions for food-regulatory peptides, neuropeptide-Y (NPY) and interleukin-1ß (IL-1ß) in the hypothalamic arcuate nuclei (nARC), were quantitated by TaqMan real-time PCR. Pain sensation was measured on all four limbs and tail by the plantar test. Cognitive functions were tested in the Morris water maze (MWM). RESULTS: Levels of orexigenic ghrelin as well as mRNA expression of orexigenic NPY in nucleus arcuatus (nRC)re significantly enhanced on day 2 of AA only. Reduced body weight and food intake persisted by day 4 with the most profound reduction on day 2. The mRNA for anorexigenic IL-1ß in the nARC was significantly enhanced on days 2 and 4. Enhanced pain sensitivity was observed on day 2, as was the cognitive impairment given by longer time to find the hidden platform, longer time spent in thigmotaxis zone, and longer trajectory. The less effective strategy used to find the hidden platform was observed up to the day 4 of AA. CONCLUSIONS: Early stage of AA brings about reduced body weight, food intake, and activation of central orexigenic pathways. The observed anorexia could be ascribed to the over-expression of anorexigenic IL-1ß which dominates over the NPY orexigenic effects. On day 2 of AA higher pain sensitivity and cognitive impairment appear. All the observed change tend to recover by day 4 of the disease.

Resistin and visfatin: regulators of insulin sensitivity, inflammation and immunity.

Adipokines play a significant role in the pathogenesis of a low-grade inflammation associated with obesity and metabolic syndrome, and in chronic inflammatory and autoimmune diseases such as rheumatoid arthritis. Among variety of adipokines, resistin and visfatin are proposed as important pro-inflammatory mediators, which also interfere with the central regulation of insulin sensitivity. Resistin has been initially postulated as a risk factor for insulin resistance, however, the subsequent available data on it have revealed contradictory findings in both humans and rodents. On the other hand, visfatin has been suggested to be a beneficial adipokine with insulin-mimicking/-sensitizing effects, but regulation of visfatin production and its physiological importance in the conditions of obesity and type 2 diabetes mellitus are still not completely understood. Despite the opposing effects of resistin and visfatin on the regulation of insulin sensitivity, both adipokines have pro-inflammatory properties. Clinical and experimental studies have shown that the expression and secretion of resistin and visfatin are up-regulated during inflammation and in response to pro-inflammatory cytokines. It has also become increasingly evident that resistin as well as visfatin itself can contribute to the inflammatory processes by triggering cytokine production and NF-kappaB activation. New insight into the role of adipokines makes them attractive targets for novel therapeutic strategies in chronic inflammatory diseases or subclinical inflammation relating to obesity and various metabolic abnormalities.

Leptin and adiponectin: from energy and metabolic dysbalance to inflammation and autoimmunity.

There is a growing evidence that both overnutrition and undernutrition negatively interfere with immune system. The overnutrition has been found to increase susceptibility to the development of inflammatory or autoimmune diseases. On the other hand, starvation or malnutrition has been more associated with increased susceptibility to infections. In the regulation of immune and inflammatory processes, white adipose tissue plays a critical role as an endocrine organ which produces number of active peptides, called adipokines. The adipokines, leptin and adiponectin represent a critical link among nutritional status, metabolism and immunity. Leptin is primarily known as a satiety factor regulating body weight by suppression of appetite and stimulation of energy expenditure, and its serum levels and gene expression in adipocytes strongly correlate with proportion of body fat stores. On the other hand, leptin is a pro-inflammatory adipokine inducing T helper 1 cells and may contribute to the development and progression of autoimmune responses. Adiponectin plays an important role as an insulin-sensitizing adipokine which production is decreased in obesity and in conditions associated with insulin resistance. Adiponectin also acts as an anti-inflammatory factor especially with regard to atherosclerosis, but in some chronic inflammatory/autoimmune diseases adiponectin may have pro-inflammatory effects and its production correlates with inflammatory markers and disease activity. This review discusses the main biological activities of leptin and adiponectin as well as their contribution to inflammatory and autoimmune processes with particular focus on rheumatoid arthritis and its experimental models.

Activation of hypothalamic NPY, AgRP, MC4R, AND IL-6 mRNA levels in young Lewis rats with early-life diet-induced obesity.

OBJECTIVE: Obesity represents a low-grade inflammatory disease and appears a risk factor for insulin resistance, but little is known on whether this may contribute to the development of autoimmune inflammatory diseases. The aim of this work was to study the early-life diet-induced obesity in Lewis rats which are known to be highly susceptible to autoimmunity. METHODS: Obesity was induced by reduced litter size (4 pups per litter) followed by high-fat diet (SHF rats). Control rats (8 pups per litter) were fed with standard diet (CN rats). Oral glucose tolerance test (3 g glucose per kg b.w.) was performed by intra-gastric tube in conscious rats after 12 h fast. Adipocyte size was assessed by light microscope after collagenase digestion. Hypothalamic arcuate (ARC) and paraventricular nuclei (PVN) were isolated by the punching technique. Target mRNAs were quantified by real-time PCR with the use of TaqMan probes and primers. Serum hormones (leptin, ghrelin, adiponectin, visfatin and insulin) were assayed by specific RIAs . RESULTS: During the experimental period SHF rats had the same body weight gain and caloric intake as CN rats. At the age of 8 weeks SHF rats showed increased epididymal fat mass and adipocyte volume, impaired glucose tolerance, normal basal fasting insulin, visfatin, and ghrelin level, but decreased adiponectin and high leptin level. In the ARC, the SHF rats showed increased expression of mRNA for orexigenic neuropeptide Y (NPY), agouti-related protein (AgRP) and anorexigenic pro-inflammatory cytokine IL-6. In the PVN, the SHF rats showed increased expression of mRNA for anorexigenic melanocortin 4 receptor (MC4R) and IL-6. CONCLUSION: Overexpression of orexigenic NPY and AgRP in the ARC indicates leptin resistance in SHF rats. The increased expression of MC4R in PVN points to the activation of melanocortin anorexigenic system which, along with increased hypothalamic IL-6, might prevent the animals from overfeeding. Higher adiposity in these rats results from the high fat-diet composition and not from increased caloric intake. Furthermore, enhanced leptin production appears the main factor indicating the predisposition to autoimmunity in these overfed rats.