Neonatal overnutritional programming impairs the hypophagia and neuron activation induced by acute lipopolysaccharide in adult male rats.

Nutritional status during critical windows in early development can challenge metabolic functions and physiological responses to immune stress in adulthood, such as the systemic inflammation induced by lipopolysaccharide (LPS). The aim of this study was to investigate the long-term effects of post-natal over- and undernutrition on the anorexigenic effect of LPS and its association with neuronal activation in the brainstem and hypothalamus of male rats. Animals were raised in litters of 3 (small - SL), 10 (normal - NL), or 16 (large - LL) pups per dam. On post-natal day 60, male rats were treated with LPS (500 µg/Kg) or vehicle for the evaluation of food intake and c-Fos expression in the area postrema (AP), nucleus of solitary tract (NTS), and paraventricular (PVN), arcuate (ARC), ventromedial (VMH), and dorsomedial (DMH) nuclei of the hypothalamus. SL, NL, and LL animals showed a decreased food consumption after LPS treatment. In under- and normonourished animals, peripheral LPS induced an increase in neuronal activation in the brainstem, PaV, PaMP, and ARC and a decrease in the number of c-Fos-ir neurons in the DMH. Overnourished rats showed a reduced hypophagic response, lower neuron activation in the NTS and PaMP, and no response in the DMH induced by LPS. These results indicate that early nutritional programming displays different responses to LPS, by means of neonatal overnutrition decreasing LPS-mediated anorexigenic effect and neuronal activation in the NTS and hypothalamic nuclei.

Hydrogel-Containing Biogenic Silver Nanoparticles: Antibacterial Action, Evaluation of Wound Healing, and Bioaccumulation in Wistar Rats.

Wound infections are feared complications due to their potential to increase healthcare costs and cause mortality since multidrug-resistant bacteria reduce treatment options. This study reports the development of a carbomer hydrogel containing biogenic silver nanoparticles (bioAgNPs) and its effectiveness in wound treatment. This hydrogel showed in vitro bactericidal activity after 2 h, according to the time-kill assay. It also reduced bacterial contamination in rat wounds without impairing their healing since the hydrogel hydrophilic groups provided hydration for the injured skin. The high number of inflammatory cells in the first days of the skin lesion and the greater degree of neovascularization one week after wound onset showed that the healing process occurred normally. Furthermore, the hydrogel-containing bioAgNPs did not cause toxic silver accumulation in the organs and blood of the rats. This study developed a bioAgNP hydrogel for the treatment of wounds; it has a potent antimicrobial action without interfering with cicatrization or causing silver bioaccumulation. This formulation is effective against bacteria that commonly cause wound infections, such as Pseudomonas aeruginosa and Staphylococcus aureus, and for which new antimicrobials are urgently needed, according to the World Health Organization's warning.

Glucocorticoids contribute to metabolic and liver impairments induced by lactation overnutrition in male adult rats.

Introduction: Lactation overnutrition is a programming agent of energy metabolism, and litter size reduction leads to the early development of obesity, which persists until adulthood. Liver metabolism is disrupted by obesity, and increased levels of circulating glucocorticoids are pointed as a possible mediator for the obesity development, since bilateral adrenalectomy (ADX) can reduce obesity in different models of obesity. Methods: This study aimed to evaluate the effects of glucocorticoids on metabolic changes and liver lipogenesis and insulin pathway induced by lactation overnutrition. For this, on the postnatal day 3 (PND), 3 pups (small litter-SL) or 10 pups (normal litter-NL) were kept with each dam. On PND 60, male Wistar rats underwent bilateral adrenalectomy (ADX) or fictitious surgery (sham), and half of ADX animals received corticosterone (CORT- 25 mg/L) diluted in the drinking fluid. On PND 74, the animals were euthanized by decapitation for trunk blood collection, and liver dissection and storage. Results and Discussion: SL rats presented increased corticosterone, free fatty acids, total and LDL-cholesterol plasma levels, without changes in triglycerides (TG) and HDL-cholesterol. The SL group also showed increased content of liver TG, and expression of fatty acid synthase (FASN), but decreased expression of PI3Kp110 in the liver, compared to NL rats. In the SL group, the ADX decreased plasma levels of corticosterone, FFA, TG and HDL cholesterol, liver TG, and liver expression of FASN, and IRS2, compared to sham animals. In SL animals, CORT treatment increased plasma levels of TG and HDL cholesterol, liver TG, and expression of FASN, IRS1, and IRS2, compared with the ADX group. In summary, the ADX attenuated plasma and liver changes observed after lactation overnutrition, and CORT treatment could reverse most ADX-induced effects. Thus, increased circulating glucocorticoids are likely to play a pivotal role in liver and plasma impairments induced by lactation overnutrition in male rats.

Differential benefits of physical training associated or not with l-arginine supplementation in rats with metabolic syndrome: Evaluation of cardiovascular, autonomic and metabolic parameters.

Metabolic syndrome (MetS) is characterized by endocrine-metabolic and cardiac alterations that increase the risk of cardiovascular disease, dyslipidemia, and type-2 diabetes mellitus. Dietary supplementation with l-Arginine (L-Arg) is beneficial for fat loss, while chronic aerobic exercise has several benefits in reversing cardiovascular, autonomic, and metabolic dysfunctions caused by obesity. However, the association between these two approaches has not yet been described. This study aimed to evaluate the possible benefits of physical training, with or without l-Arg-supplementation, on cardiovascular, autonomic, and metabolic parameters in rats with MetS, which was induced by the subcutaneous administration of monosodium glutamate at 4 mg g-1day-1 in rats from the first to fifth day of life. Physical training on a treadmill and supplementation with l-Arg-in adulthood were carried out concomitantly for 8 weeks. After this, the animals underwent femoral artery catheterization to record their cardiovascular parameters and autonomic modulation. Organs and blood were removed to measure levels of nitrite, glucose, and hepatic steatosis. In adult rats with MetS, supplementation with l-Arg-in combination with physical training reduced hypertension, tachycardia, adipose tissue mass, free fatty acids, and hepatic steatosis. Supplementation with l-Arg-and physical training separately was beneficial in reducing several aspects of MetS, but a combination of both was especially effective in reducing adipose tissue and hepatic steatosis. Together, the two therapies can form a good strategy to combat MetS.

Neonatal overnutrition, but not neonatal undernutrition, disrupts CCK-induced hypophagia and neuron activation of the nucleus of the solitary tract and paraventricular nucleus of hypothalamus of male Wistar rats.

Metabolic programming may be induced by reduction or enhancement of litter size, which lead to neonatal over or undernutrition, respectively. Changes in neonatal nutrition can challenge some regulatory processes in adulthood, such as the hypophagic effect of cholecystokinin (CCK). In order to investigate the effects of nutritional programming on the anorexigenic function of CCK in adulthood, pups were raised in small (SL, 3 pups per dam), normal (NL, 10 pups per dam), or large litters (LL, 16 pups per dam), and on postnatal day 60, male rats were treated with vehicle or CCK (10 µg/Kg) for the evaluation of food intake and c-Fos expression in the area postrema (AP), nucleus of solitary tract (NTS), and paraventricular (PVN), arcuate (ARC), ventromedial (VMH), and dorsomedial (DMH) nuclei of the hypothalamus. Overnourished rats showed increased body weight gain that was inversely correlated with neuronal activation of PaPo, VMH, and DMH neurons, whereas undernourished rats had lower body weight gain, inversely correlated with increased neuronal activation of PaPo only. SL rats showed no anorexigenic response and lower neuron activation in the NTS and PVN induced by CCK. LL exhibited preserved hypophagia and neuron activation in the AP, NTS, and PVN in response to CCK. CCK showed no effect in c-Fos immunoreactivity in the ARC, VMH, and DMH in any litter. These results indicate that anorexigenic actions, associated with neuron activation in the NTS and PVN, induced by CCK were impaired by neonatal overnutrition. However, these responses were not disrupted by neonatal undernutrition. Thus, data suggest that an excess or poor supply of nutrients during lactation display divergent effects on programming CCK satiation signaling in male adult rats.

Vasoactive intestinal peptide promotes hypophagia and metabolic changes: Role of paraventricular hypothalamic nucleus and nitric oxide.

Vasoactive intestinal peptide (VIP), a neuromodulator present in the hypothalamus, plays an important role in the regulation of food intake. Paraventricular nucleus of the hypothalamus (PVN) is involved in ingestive responses and regulates the nitric oxide (NO) pathway. The main objectives of this study were to investigate metabolic changes established after different doses and times of VIP microinjection on the PVN, and the effect of VIP microinjection on the PVN on food intake and the role of NO in this control. In anesthetized rats, increased blood plasma glucose and insulin levels were observed following the doses of 40 and 80 ng/g of body weight. At the dose of 40 ng/g, VIP promoted hyperglycemia and hyperinsulinemia 5, 10, and 30 min after microinjection, and increased free fatty acids and total lipids plasma levels after 5 min, and triglycerides after 10 min. In awake animals, once again, VIP administration increased plasmatic levels of glucose, free fatty acids, corticosterone, and insulin 10 min after the microinjection. Moreover, VIP promoted hypophagia in the morning and night periods, and L-arginine (L-Arg) and monosodium glutamate (MSG) or a combination of both attenuated VIP-induced reduction on food intake. In addition, nitrate concentration in the PVN was decreased after VIP microinjection. Our data show that the PVN participates in the anorexigenic and metabolic effects of VIP, and that VIP-induced hypophagia is likely mediated by reduction of NO.

Lactation overnutrition-induced obesity impairs effects of exogenous corticosterone on energy homeostasis and hypothalamic-pituitary-adrenal axis in male rats.

AIMS: Litter size reduction on the first days of life results in increased body weight and adiposity, with higher levels of circulating glucocorticoids. Obese rodents are more sensitive to the anabolic effects of glucocorticoids and less responsive to glucocorticoids feedback on hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to evaluate effects of the treatment with corticosterone on metabolic responses and HPA axis in adult male rats reared in small litters. MAIN METHODS: From postnatal day (PND) 60 to 88, adult male rats of normal (NL- 10 pups/dam) and small (SL- 3 pups/dam) litters received oral treatment with Corticosterone (CORT-15 mg/L) in the drinking water or no treatment, composing the four experimental groups (NL-water; NL-CORT; SL-water and SL-CORT), for the evaluation of energy homeostasis and HPA axis. KEY FINDINGS: Male rats of SL-water group presented on PND88: glucose intolerance, higher adiposity, plasma triglycerides, free fatty acids, total and low-density lipoprotein (LDL) cholesterol and corticosterone. SL-water animals showed increased mRNA of corticotrophin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) and proopiomelanocortin (POMC) in the pituitary, with decreased mRNA expression of PVN mineralocorticoid receptor. NL-CORT animals presented glucose intolerance, increased body weight, food intake, total and LDL cholesterol. Glucocorticoid treatment reduced corticosterone levels and adrenal cortex thickness in NL group, associated with increased mRNA of PVN CRH and pituitary POMC, without effects on SL animals. SIGNIFICANCE: Lactation overnutrition promotes hyperreactivity of HPA axis and reduces the responsiveness to glucocorticoids effects on energy balance and negative feedback of HPA axis in adult male rats.

Arcuate nucleus of the hypothalamus contributes to the hypophagic effect and plasma metabolic changes induced by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide.

The arcuate nucleus of hypothalamus (ARC) integrates circulating factors that signal energy status. The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are widely distributed in the periphery and central nervous systems (CNS) and play important roles on energy balance. The present study aimed to investigate the responses of microinjection of VIP and PACAP in the ARC on metabolic changes and food intake. In addition, the activity of neurons in the ARC following intracerebroventricular (ICV) microinjection of these peptides was also evaluated. Microinjection of VIP or PACAP in the ARC decreased fasting-induced hyperphagia and food intake, decreased total lipids, and increased free fatty acids plasma concentrations. VIP microinjection in the ARC induced hyperglycemia and decreased total cholesterol level; and PACAP reduced triglycerides concentration. ICV microinjection of VIP and PACAP enhanced neuronal activation in the ARC, associated with lower fasting-induced hyperphagia and plasma metabolic changes (only VIP). These results suggest that VIP and PACAP play important roles in ARC, inducing hypophagia and peripheral metabolic changes, as hyperglycemia, increased free fatty acids and decreased total lipids plasma levels.

Gluconeogenesis is reduced from alanine, lactate and pyruvate, but maintained from glycerol, in liver perfusion of rats with early and late sepsis.

Sepsis induces several metabolic abnormalities, including hypoglycaemia in the most advanced stage of the disease, a risk factor for complications and death. Although hypoglycaemia can be caused by inhibition of hepatic gluconeogenesis, decreased and increased gluconeogenesis were reported in sepsis. Furthermore, gluconeogenesis from glycerol was not yet evaluated in this disease. The main purpose of this study was to investigate the gluconeogenesis from alanine, lactate, pyruvate and glycerol in rats with early (8 hours) and late (18 hours) sepsis. Parameters related to the characterization of sepsis were also evaluated. Sepsis was induced by cecal ligation and puncture and gluconeogenesis was assessed in liver perfusion. Rats with early and late sepsis showed increased lactataemia, depletion of liver glycogen and peripheral insulin resistance, characterizing the establishment of sepsis. Rats with early and late sepsis showed decreased gluconeogenesis from alanine, lactate and pyruvate. Interestingly, gluconeogenesis from glycerol, a precursor that enters in the pathway at a later step, subsequent to the entry of alanine, lactate and pyruvate, was maintained in rats with early and late sepsis. In conclusion, gluconeogenesis is decreased from alanine, lactate and pyruvate, but maintained from glycerol, in liver perfusion of rats with early and late sepsis. SIGNIFICANCE OF THE STUDY: The maintenance of gluconeogenesis from glycerol, but not from alanine, lactate and pyruvate, together with the liver glycogen depletion, points the glycerol as an important precursor for the maintenance of glycaemic homeostasis in sepsis. The findings open the possibility of further investigation on the administration of glycerol in the treatment of hypoglycaemia associated with more advanced sepsis.

Neonatal overfeeding reduces estradiol plasma levels and disrupts noradrenergic-kisspeptin-GnRH pathway and fertility in adult female rats.

This work evaluated the effects of neonatal overfeeding, induced by litter size reduction, on fertility and the noradrenaline-kisspeptin-gonadotrophin releasing hormone (GnRH) pathway in adult female rats. The litter size was adjusted to 3 pups with each mother in the small litters (SL) and 10 pups with each mother in the normal litters (NL). SL females exhibited metabolic changes associated with reproductive dysfunctions, shown by earlier vaginal opening and first estrus, later regular cyclicity onset, and lower and higher occurrences of estrus and diestrus phases, respectively, as well as reduced fertility, estradiol plasma levels, and mRNA expressions of tyrosine hydroxylase in the locus coeruleus, kisspeptin, and GnRH in the preoptic area in adult females in the afternoon of proestrus. These results suggest that neonatal overfeeding in female rats promotes reproductive dysfunctions in adulthood, such as lower estradiol plasma levels associated with impairments in fertility and noradrenaline-kisspeptin-GnRH pathway during positive feedback.

Unexpected Thiocyanate Adsorption onto Ferrihydrite Under Prebiotic Chemistry Conditions.

The most crucial role played by minerals was in the preconcentration of biomolecules or precursors of biomolecules in prebiotic seas. If this step had not occurred, molecular evolution would not have occurred. Thiocyanate is an important molecule in the formation of biomolecules as well as a catalyst for prebiotic reactions. The adsorption of thiocyanate onto ferrihydrite was carried out under pH and ion composition conditions in seawater that resembled those of prebiotic Earth. The seawater used in this work had high Mg2+, Ca2+ and SO42- concentrations. The most important result of this work was that ferrihydrite adsorbed thiocyanateata pH value (7.2 ± 0.2) that usually does not adsorb thiocyanate. The high adsorptivity of Mg2+, Ca2+ and SO42-onto ferrihydrite showed that seawater ions can act as carriers of thiocyanate to the ferrihydrite surface, creating a huge outer-sphere complex. Kinetic adsorption and isotherm experiments showed the best fit for the pseudo-second-order model and an activation energy of 23.8 kJ mol-1forthe Langmuir-Freundlich model, respectively. Thermodynamic data showed positive ΔG values, which apparently contradict the adsorption isotherm data and kinetic data that was obtained. The adsorption of thiocyanate onto ferrihydrite could be explained by coupling with the exergonic SO42- adsorption onto ferrihydrite. The FTIR spectra showed no difference between the C≡N stretching peaks of adsorbed thiocyanate and free thiocyanate, corroborating the formation of an outer-sphere complex. All the results demonstrated the importance of the artificial seawater composition for the adsorption of thiocyanate and for understanding prebiotic chemistry.

Adrenalectomy impairs vasoactive intestinal peptide-induced changes in food intake and plasma parameters.

PURPOSE: The aim of this study is to evaluate the effects of adrenalectomy (ADX) and glucocorticoid in the changes induced by intracerebroventricular (ICV) administration of vasoactive intestinal peptide (VIP) on food intake and plasma parameters, as well as VIP receptor subtype 2 (VPAC2) mRNA expression in different hypothalamic nuclei of male rats. METHODS: Male Wistar rats (260-280 g) were subjected to ADX or sham surgery, 7 days before the experiments. Half of ADX animals received corticosterone (ADX + CORT) in the drinking water. Animals with 16 h of fasting received ICV microinjection of VIP or saline (0.9% NaCl). After 15 min: (1) animals were fed, and the amount of food ingested was quantified for 120 min; or (2) animals were euthanized and blood was collected for biochemical measurements. Determination of VPAC2 mRNA levels in LHA, ARC, and PVN was performed from animals with microinjection of saline. RESULTS: VIP treatment promoted the anorexigenic effect, which was not observed in ADX animals. Microinjection of VIP also induced an increase in blood plasma glucose and corticosterone levels, and a reduction in free fatty acid plasma levels, but adrenalectomy abolished these effects. In addition, adrenalectomy reduced mRNA expression of VPAC2 in the lateral hypothalamic area and arcuate nucleus, but not in the paraventricular nucleus. CONCLUSIONS: These results suggest that adrenal glands are required for VIP-induced changes in food intake and plasma parameters, and these responses are associated with reduction in the expression of VPAC2 in the hypothalamus after adrenalectomy.

Sex differences in glucocorticoids-induced anabolic effects in rats.

Glucocorticoids (GC) increase food intake and body weight in humans and rodents and chronic stress and GC treatment-induced enhancement of the plasma concentration of GC lead to obesity and metabolic changes. In response to hypercaloric treatment, males were shown to be more susceptible to obesity than females, demonstrating that sex differences may affect energy homeostasis. The objective of the current study was to evaluate the effects of prolonged (28 days) treatment with dexamethasone or corticosterone on food intake and body weight gain in intact rats, both male and female. Also examined were Lee index, weights and area of adipocytes of retroperitoneal and perigonadal+perirenal adipose tissues, glucose tolerance test (GTT) and plasma concentrations of free fatty acids, cholesterol and triglycerides. Treatment with dexamethasone was able to increase body weight, food intake, area of adipocytes and weight of retroperitoneal adipose tissue in males. Prolonged treatment with corticosterone also stimulated body weight gain and food intake in males. In addition, it induced an increase in the area of adipocytes and weight of perirenal+perigonadal adipose tissue and higher glycemia after GTT in these animals, without changes on Lee index and plasma parameters after both GC treatments. No parameter was changed by dexamethasone or corticosterone treatment in female rats. Thus, it can be concluded that male rats are more susceptible to the anabolic effects of glucocorticoids than female rats, and these responses can be due to the protective effects of circulating estrogens in females, and/or the difference between males and females in the expression/activity of corticosteroids receptors.

The effect of pH and ionic strength on the adsorption of glyphosate onto ferrihydrite.

Although, glyphosate (N-(phosphonomethyl) glycine) is one of the most widely used herbicides in the world, its interaction with poorly crystalline iron oxides, such as ferrihydrite, is not well studied. In this research, we examined the adsorption of glyphosate onto ferrihydrite using infrared spectroscopy (FT-IR), electron paramagnetic resonance spectroscopy (EPR), adsorption kinetic models and adsorption isotherm models. The effect of pH and sodium chloride concentration on the adsorption of glyphosate onto ferrihydrite as well as the effect of extractors (CaCl2 0.010 mol L-1 and Mehlich) on the desorption of glyphosate were also evaluated. There are two important findings described in this work. First, 84% of adsorbed glyphosate strongly interacted to ferrihydrite as an inner-sphere complex and phosphate and amine groups are involved in this interaction. Second, an increase of sodium chloride salt concentration increased the adsorption of glyphosate onto ferrihydrite. The non-linear Langmuir model and pseudo second order model showed a good agreement of theoretical limit of glyphosate adsorbed onto ferrihydrite, 54.88 µg mg-1 and 48.8 µg mg-1, respectively. The adsorption of glyphosate onto ferrihydrite decreased when the pH increased. Under the conditions used in this work, EPR spectra did not show dissolution of ferrihydrite. Surface area, pore volume and pHpzc of ferrihydrite decreased after adsorption of glyphosate.

WITHDRAWN: Sex differences in glucocorticoids-induced anabolic effects on energy balance.

This article has been withdrawn: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been withdrawn at the request of the editor and publisher. The publisher regrets that an error occurred which led to the premature publication of this paper. This error bears no reflection on the article or its authors. The publisher apologizes to the authors and the readers for this unfortunate error.

Estradiol protects against ovariectomy-induced susceptibility to the anabolic effects of glucocorticoids in rats.

Glucocorticoids increase appetite and body weight gain in rats and ovariectomy (OVX) induces obesity, while estrogen (E) replacement attenuates OVX-induced changes. It is known that animals with obesity are more responsive to glucocorticoids anabolic effects than lean ones. This study aimed to evaluate the effects of ovariectomy and the protective role of estradiol on the responses induced by prolonged treatment with corticosterone or dexamethasone on energy homeostasis. For this, female Wistar rats subjected to SHAM or OVX surgery, composing the SHAM, OVX, and OVX + E groups, received water/ETOH or corticosterone (15 mg/l) and water or dexamethasone (0.5 µg/l) as drinking fluid for 28 days. The OVX + E group, since the first day, was daily treated with estradiol (10 µg/0.2 ml/rat SC). OVX induced enhancement of body weight gain, food intake, area of the adipocytes and weight of retroperitoneal adipose tissue, plasma cholesterol and glucose intolerance, with reduction on uterus weight. In OVX animals, treatment with glucocorticoids induced increases on body weight gain, food intake, weight of retroperitoneal adipose tissue, area of adipocytes of retroperitoneal and perigonadal + perirenal fat depots, plasma triglycerides (corticosterone), and glycemic response after GTT (dexamethasone), with minor effects on SHAM group. Estradiol treatment to OVX rats prevented these effects induced by glucocorticoids, in addition to decrease body weight gain, fat accumulation and glucose intolerance, and to increase weight of uterus, triglycerides and free fatty acids plasma levels. These data demonstrate that protection against glucocorticoids-induced anabolic responses in females is eliminated by ovariectomy and estradiol can prevent these responses.

Corticotrophin-releasing factor mediates vasoactive intestinal peptide-induced hypophagia and changes in plasma parameters.

Vasoactive intestinal peptide (VIP) and corticotrophin-releasing factor (CRF) are anorexigenic neuropeptides that act in the hypothalamus to regulate food intake. Intracerebroventricular (ICV) microinjection of VIP promotes increased plasma adrenocorticotrophic hormone (ACTH) and corticosterone, indicating that VIP activates hypothalamic-pituitary-adrenal axis. The aim of this study was to evaluate the interaction between VIP and CRF, by verifying the effects of ICV administration of VIP on the activity of neurons and CRF mRNA expression in paraventricular nucleus of hypothalamus (PVN). In addition, it was evaluated the effects of pretreatment with CRF type 1 receptor (CRFR1) antagonist (Antalarmin, ANT) or CRF type 2 receptor (CRFR2) antagonist (Antisauvagine-30, AS30) on VIP-induced changes on food intake and plasma parameters of male rats. Compared to Saline group, VIP increased not only the number of Fos-related antigens (FRA)-immunoreactive neurons in the PVN but also CRF mRNA levels in this nucleus. Both ANT and AS30 treatment attenuated the inhibition of food intake promoted by VIP, ANT showing a more pronounced effect. Both antagonists also attenuated VIP-induced reduction and enhancement of free fatty acids and corticosterone plasma levels, respectively, and only AS30 was able to attenuate the hyperglycemia. These results suggest that CRF is an important mediador of VIP effects on energy balance, and CRFR1 and CRFR2 are involved in these responses.

Oxytocin participates on the effects of vasoactive intestinal peptide on food intake and plasma parameters.

Vasoactive intestinal peptide (VIP) is a neurotransmitter with anorectic effect that acts in the hypothalamus to regulate food intake. Oxytocin is a neuropeptide produced in the hypothalamus that controls energy homeostasis and has an inhibitory role on food intake. Thus, the present study aims at verifying the role of oxytocin as a mediator of VIP on energy homeostasis. For this purpose, intracerebroventricular microinjection of oxytocin receptor antagonist (vasotocin, OVT) or vehicle (NaCl 0.9%) was carried out in male rats, and after 15 min, VIP or saline was microinjected. After 15 min of the second microinjection, food intake was evaluated or euthanasia was undertaken for blood collection. There was a reduction on food intake after VIP microinjection and the pretreatment with OVT partially reversed this effect. Hyperglycemia was observed after VIP microinjection, and pretreatment with OVT partially blocked this effect. Plasma corticosterone concentration was significantly increased after VIP or OVT. Plasma levels of free fatty acids were decreased by VIP, but not when VIP was microinjected after OVT. Thus, OVT partially reversed VIP-induced hypophagia and changes on plasma metabolic parameters, suggesting a role for oxytocin as a mediator of VIP effects on energy homeostasis.

Pioglitazone improves insulin sensitivity and reduces weight loss in Walker-256 tumor-bearing rats.

AIM: The lipogenic effect of pioglitazone (PGZ), an insulin (INS) sensitizer, is well established. However, few studies have evaluated PGZ effects in preventing weight loss in cancer. We investigated PGZ effects, alone or associated with INS, on INS resistance, cachexia and metabolic abnormalities induced by Walker-256 tumor in rats. MAIN METHODS: PGZ (5.0mg·kg-1, oral) or PGZ+INS (NPH, 1.0UI·kg-1, sc), were once-daily administered during 12days, starting on the day inoculation of Walker-256 tumor cells. Rats were separated in small (about 17g) and big (about 30g) tumor-bearing. KEY FINDINGS: Big tumor-bearing rats showed greater cachexia, blood triacylglycerol and free fatty acids and INS resistance. PGZ and PGZ+INS treatments did not change tumor growth and food intake, but reduced several abnormalities such as INS resistance, increased blood free fatty acids, retroperitoneal fat wasting and body weight loss in small tumor-bearing rats. The prevention of retroperitoneal fat wasting did not involve reduction of tumor necrosis factor-α expression increased. In big tumor-bearing rats, PGZ and PGZ+INS treatments reversed the high blood triacylglycerol and free fatty acids levels, but had no effect on other parameters. SIGNIFICANCE: PGZ and PGZ+INS improved INS peripheral sensitivity, possibly by decreasing blood free fatty acids, and reduced fat tissue wasting and body weight loss in small tumor-bearing rats. The results suggest clinical benefits of PGZ in preventing INS resistance, adipose tissue wasting and weight loss when the tumor is small, i.e., in less severe cachexia.