Naltrexone/bupropion modifies weight, food intake, and Drd2 gene expression in rats.

Obesogenic diets are known to induce obesity and changes in food intake in experimental animals. Obesity negatively affects the peripheral metabolism and neural aspects, such as changes in eating behavior. In obese animals, dopamine (DA) receptor levels are reduced. DA is one of the main peptides involved in the motivation and pleasure of eating. A combination of naltrexone/bupropion (NB) has shown promise in controlling metabolic alterations, but there are few studies on how they modulate dopaminergic expression. NB, in addition to reducing food intake and body weight, can modify tyrosine hydroxylase (Th) and DA receptor D2 (Drd2) levels in the mesolimbic areas of rats submitted to a high-fat diet (HF). The study evaluated the effect of NB on food intake, body weight, and expression levels of Th, Drd1a, and Drd2, in the nucleus accumbens and striatum of rats fed on HF diet. Wistar rats were grouped according to diet: standard (n = 20) and HF diet (n = 20). The food intake and body weight were analyzed. The gene expression of Th, Drd1a, and Drd2 was evaluated using real-time PCR. NB combination of 1 mg/kg and 20 mg/kg reduced food intake and body weight, increased Drd2 expression in rats on HF diet, and increased Th in rats on both experimental diets. The level of Drd1a was unchanged. We concluded that bodyweight reduction may be associated with decreased food intake in response to the increased Drd2 expression in the mesolimbic areas of rats that received an HF diet.

Hypothalamic peptide and nutrient sensors gene expression in the hypothalamus of neonatal rat.

In the neonate, the main mediator for satiety or hunger is the information of distention or gastric contraction. Food intake controls has two types of a short-term one, based on the level of hydration, and another long-term one, dependent on the gastric stretch. The aim of this study is to evaluate the gene expression of peptides and nutrient sensors in the hypothalamus at 10 and 18 days of postnatal life. Male rats divided into groups: Fasting, Water, Milk, and Gavage.Two age groups had analyzed into 10 and 18 days. Gene expression of hypothalamic peptides, Neuropeptide Y(NPY), Agouti-related peptide(AgRP), proopiomelanocortin(POMC), cocaine-and amphetamine-regulated transcript(CART), and energy sensors mechanistic target of rapamycin(mTOR) and AMP-activated protein kinase(AMPK) in the hypothalamus was seen. During the fasting period, there was an increase in expression of AMPK seen in 10 and 18 days, also mTOR reduction. Expression of NPY, AgRP, and POMC suffered the fasting effect only at 18 days. The effect of gastric distention and energy loads, there was increased expression of AMPK at 10 and 18 days, but expression of mTOR showed only at 18 days. There was increased NPY expression at 18 days, but not at 10 days, while AgRP increased its expression at both ages. At 10 days gene expression of CART increased and POMC as well as 10-18 days. Data demonstrated a simultaneous responsiveness to hypothalamic nutrient sensing also, controlling peptide food consumption even at an early age. The mature standard of control only observed at 18 days of life.

Daytime increase in caloric intake without change in total 24-h caloric intake can increase adiposity but not total bodyweight in rats with inverted feeding pattern.

The goal of this study was to evaluate the effect of the food availability period on body weight, self-selection of macronutrients, adiposity, lipoprotein, and serum glucose profiles without changing energy intake. Young male rats were divided into 2 groups according to the availability of food during the light and dark phases of the cycle, forming 2 groups: control group (CG) and group with inverted feeding pattern (IFPG). Before inversion of food availability on the 80th day, circadian food intake was measured every 4 h over 24 h during 3 days. The glycemic curve, an oral test for glucose tolerance, and self-selection of macronutrients were evaluated. Blood samples were collected for analysis of fasting glucose, triglycerides, and total cholesterol fractions. The IFPG showed an increase in fasting glucose in the dark phase of the cycle, changes in the glycemic curve, and oral glucose tolerance test. It also showed increased abdominal and liver fat and distinct choice of macronutrients compared with the CG. A change in the availability of food according to the phase of the circadian cycle produces changes in glucose and feeding circadian rhythm culminating in increased abdominal and hepatic fat. These effects can increase the risk of metabolic disorders and installation of chronic diseases.

Non-traditional biomarkers of eating disorder symptoms among female college students.

Background: Eating disorders (ED) are often diagnosed at an advanced stage because traditional symptoms related to unhealthy eating habits are poorly recognized. ED may be also associated with non-traditional and objective biomarkers, which could prove an important screening tool to support health care professionals in diagnosing, treating, and ultimately preventing ED. Aim: To investigate the association between non-traditional physiological ED biomarkers and symptoms of ED among female college students. Methods: This study included 113 female college students, aged 18 to 23 years, enrolled in their first semester as a Bachelor of Health Sciences undergrad at public universities in the urban zone of Recife, Brazil. Symptoms of ED were measured by self-report questionnaires. Circulating levels of IL-6, IL-10, leptin, insulin, ghrelin, PYY and adiponectin were assessed using commercial immunoassays. Results: Students with symptoms of an ED exhibited higher values of IL-6 (p = 0.03) and leptin (p < 0.001) compared to those without symptoms. A positive correlation was found between leptin levels and bulimia nervosa (r = 0.42; p = 0.00), between leptin levels and binge eating (r = 0.38; p = 0.00), and between IL-6 concentrations and binge eating (r = 0.25; p = 0.04). Multiple linear regression analysis with anorexia nervosa, bulimia nervosa and binge eating as dependent variables showed that IL-6 and leptin best explained ED symptoms, even when adjusted for body mass index (BMI). Conclusions: These findings suggest that peripheral peptides, namely leptin and IL-6, are associated with symptoms of ED in female college students. Future studies are needed to determine if there is a causal relationship between these biomarkers and the onset of ED. Relevance for patients: If future longitudinal studies demonstrate causality between the biomarkers assessed here and ED symptoms, these serum makers could be used as screening tool for inappropriate eating behavior. This may in turn improve the early diagnosis, treatment, and, ultimately, the prognosis of patients with ED.

Maternal protein restriction during gestation and lactation in the rat results in increased brain levels of kynurenine and kynurenic acid in their adult offspring.

Early malnutrition is a risk factor for depression and schizophrenia. Since the offspring of malnourished dams exhibit increased brain levels of serotonin (5-HT), a tryptophan-derived neurotransmitter involved in the pathophysiology of these mental disorders, it is believed that the deleterious effects of early malnutrition on brain function are due in large part to altered serotoninergic neurotransmission resulting from impaired tryptophan (Trp) metabolism. However, tryptophan is also metabolized through the kynurenine (KYN) pathway yielding several neuroactive compounds including kynurenic (KA), quinolinic (QA) and xanthurenic (XA) acids. Nevertheless, the impact of perinatal malnutrition on brain kynurenine pathway metabolism has not been examined to date. Here, we used ultra-performance liquid chromatography-tandem mass spectrometry for the simultaneous quantification of tryptophan and a set of seven compounds spanning its metabolism through the serotonin and kynurenine pathways, in the brain of embryos and adult offspring of rat dams fed a protein-restricted (PR) diet. Protein-restricted embryos showed reduced brain levels of Trp, serotonin and KA, but not of KYN, XA, or QA. In contrast, PR adult rats exhibited enhanced levels of Trp in the brainstem and cortex along with increased concentrations of 5-HT, kynurenine and XA. The levels of XA and KA were also increased in the hippocampus of adult PR rats. These results show that early protein deficiency induces selective and long-lasting changes in brain kynurenine metabolism. Given the regulatory role of KYN pathway metabolites on brain development and function, these changes might contribute to the risk of developing psychiatric disorders induced by early malnutrition.

Effects of perinatal protein malnutrition and fenfluramine action on food intake and neuronal activation in the hypothalamus and raphe nuclei of neonate rats.

In neonatal rats, hunger and satiety responses occur particularly via dehydration and gastric distention, respectively. The control of food intake in newborns is yet to be fully consolidated, particularly with respect to the participation of the hypothalamic nuclei and their relationship with the serotonergic pathway. Moreover, it is unclear how the environmental stressors in early life, like undernutrition, interfere in these events. Therefore, this study examined the serotonin-system's impact on food intake in rat neonates at postnatal day (P) 10 and P18 and the manner in which protein undernutrition during pregnancy and lactation interferes in this behavior. To accomplish this, Wistar rats were used, nutritionally manipulated by a diet having two protein levels, (8% and 17%) during pregnancy and lactation, to form the Control (n=10) and Low protein groups (n=10). At 10 and 18 postnatal days pups received an acute dose of fenfluramine (3mg/kg) or saline (0.9% NaCl) and subjected to milk consumption testing and then perfused to obtain the brains for the analysis of cell activation of the immunoreactive c-Fos in the hypothalamic and raphe nuclei. At 10days a reduction in weight gain was observed in both groups. On comparison of the neuronal activation for the paraventricular nucleus, an increased activation in response to fenfluramine was observed. At 18days, the weight gain percentage differed between the groups according to the nutritional manipulation, in which the control animals had no significant change while the undernourished presented increased weight gain with the use of fenfluramine. The marking of c-Fos in response to fenfluramine in the hypothalamic and raphe nuclei revealed, an especially lower activation of the PVN, MnR and DR compared intra-group. However when evaluating the effect of undernutrition, marking activation was observed to increase in all the nuclei analyzed, in the hypothalamus and raphe. Data from this study indicate that the action of serotonin via food intake in the neonates may have been delayed by early protein undernutrition.

Can early protein restriction induce the development of binge eating?

We tested the hypothesis that perinatal undernourishment is a factor for binge eating. At 52 days rats born from dams fed on 17% protein (Control) or 8% protein (Undernourished) were distributed into four groups, two of which continued to be fed ad libitum chow and two were submitted to three consecutive Restricted/Refeeding (R/R) cycles. According to the following schedule: Control Naïve (from mothers fed 17% protein/no restriction phase); Control Restricted (from mothers fed 17% protein/restriction phase); Undernourished Naïve (from mothers fed 8% protein/no restriction phase); and Undernourished Restricted (from mothers fed 8% protein/restriction phase). Each cycle consisted of a restriction phase (in the first four days 40% of the mean daily individual chow intake was offered for consumption), followed by a refeeding phase (4 days of chow ad libitum). After the three cycles, all animals were subjected to a feeding test (chow diet and palatable food ad libitum for 24h). During the feeding test, the Undernourished Restricted demonstrated rebound hyperphagia during 2, 4 and 6h. These results suggest the perinatal undernourishment cannot contribute to a binge eating phenotype.

Nursing Staff Members Mental's Health and Factors Associated with the Work Process: An Integrative Review.

BACKGROUND: The mental health of nursing staff members influences the work process outcomes. OBJECTIVE: Identify the work related factors that harms the nursing team's mental health. METHODS: Databases PubMed, Scopus, CINAHL and MEDLINE, by mating between the indexed descriptors in MeSH terms "mental health" and "occupational health nursing". 783 articles were rescued to give a final sample of 18 articles. Integrative review in order to identify factors associated with the work process of the nursing staff that negatively affects mental health. RESULTS: The main associated factors were work demands, psychological demands, violence, aggression, poor relationships with administrators, accidents involving the risk of exposure to HIV, stress and errors in the execution of labor activities. The main findings regarding the nursing staff's mental health were post-traumatic stress disorder, depression, stress, major depressive episode and generalized anxiety disorder. CONCLUSION: Occupational nurses need to understand the complexities of mental health problems and substance use among nursing staff members to recognize, identify and care for workers at risk and offer adequate mental health care. Although the researches interests in this theme have increased, proving that all these factors contribute to the risk to mental health of nursing professionals, the protective measures and care are being neglected by managers in both private and public network . The health of nursing workers in question here is one more challenge for a profession that takes care of others in need, therefore, requires some caring with their own health.

Fluoxetine treatment of rat neonates significantly reduces oxidative stress in the hippocampus and in behavioral indicators of anxiety later in postnatal life.

The brain, more than any other organ in the body, is vulnerable to oxidative stress damage, owing to its requirement for high levels of oxygenation. This is needed to fulfill its metabolic needs in the face of relatively low levels of protective antioxidants. Recent studies have suggested that oxidative stress is directly involved in the etiology of both eating and anxiety behavior. The aim of this study was to evaluate the effect of fluoxetine-inhibited serotonin reuptake in nursing rat neonates on behavior and on oxidative stress in the hypothalamus and the hippocampus; brain areas responsible for behavior related to food and anxiety, respectively. The results show that increased serotonin levels during a critical period of development do not induce significant differences in food-related behavior (intake and satiety), but do result in a in a significant decrease in anxiety. Measurements of oxidative stress showed a significant reduction of lipid peroxidation in the hippocampus (57%). In the hypothalamus, antioxidant enzymes were unchanged, but in the hippocampus, the activity of catalase and glutathione-S-transferase was increased (80% and 85% respectively). This suggests that protecting neural cells from oxidative stress during brain development contributes to the anxiolytic effects of serotonin.

Effects of a westernized diet on the reflexes and physical maturation of male rat offspring during the perinatal period.

This study evaluates the effects of a westernized diet during the perinatal period on the maternal performance and growth and development of rat offspring. Female Wistar rats were fed with either a control (C) diet, with casein as the protein source or a westernized (W) diet, during pregnancy and lactation. The pups were divided, eight per group, into the same diet groups as their dams. During lactation, the body weight (day 1, W = 6.85 ± 0.62 g, C = 5.81 ± 0.49, p < 0.05; day 21, W = 55.42 ± 3.78, C = 47.75 ± 3.45, p < 0.001) and somatic growth (body length day 1, W = 53.24 ± 2.16, C = 50.641 ± 1.79, p < 0.05; day 21, W = 124.8, C = 119.903 ± 3.71, p < 0.001) in the male offspring showed significant differences among the groups. The physical appearance and reflex maturation showed differences between day 1 and day 3. With the westernized diet, during the perinatal period, no alterations in maternal weight gain, gestation or performance were observed; however, changes in the coefficients of feed efficiency and energy during lactation were noted. Besides, blood glucose was found to be elevated at the end of lactation (C = 3.67 ± 0.35 mmol/l, W = 5.2 0 ± 0.49 mmol/l). At 21 days, the male pups from the dams on the westernized diet were 15 % heavier, and the maturation of the neural reflexes and physical characteristics were found to occur earlier. Therefore, the consumption of a westernized diet during the perinatal period was independent of maternal energy intake, and influenced the growth and development of offspring.

Acute effects of aerobic exercise on mood and hunger feelings in male obese adolescents: a crossover study.

BACKGROUND: The aim of this study was to determine the acute effects of exercise intensity on anxiety, mood states and hunger in obese adolescents. METHODS: Subjects were eight male obese adolescents (age 15.44 ± 2.06 y; BMI 33.06 ± 4.78 kg/m2). Each subject underwent three experimental trials: (1) Control, seated for 30 min; (2) Low intensity exercise (LIE)--exercise at 10% below ventilatory threshold (VT); (3) High intensity exercise (HIE)--exercise at 10% above VT. Anxiety (STAI Trait/State), mood (POMS) and hunger (VAS) were assessed before and immediately after the experimental sessions. Comparisons between trials and times were assessed using Kruskal-Wallis and Wilcoxon tests, respectively. Associations between variables were described using a Spearman test. RESULTS: The largest increase in hunger was observed after LEI (914.22%). Both exercise sessions increased anxiety, fatigue and decreased vigor (p < 0.05). CONCLUSIONS: Acute exercise bouts are associated with negative changes in anxiety and mood, and with increases in hunger in obese adolescents.

Moderate physical training attenuates muscle-specific effects on fibre type composition in adult rats submitted to a perinatal maternal low-protein diet.

AIM: To verify whether moderate physical training affects the muscle fibre composition of adult rats subjected to a low protein diet during the perinatal period. METHODS: Male Wistar rats were divided into two groups according to their mother's diet during gestation and lactation: control (17% casein, C) and low-protein (8% casein, LP). On postnatal day 60, half of each group was submitted to moderate physical training (8 weeks, 5 days/week(-1), 60 min/day(-1), at 70% of VO(2max), T) or not. After the physical training period, soleus and extensor digitorum longus (EDL) muscles were removed. Myofibrillar ATPase staining was used to classify muscle fibres as type I, IIa, IIb, and intermediate. RESULTS: In the EDL muscle, LP rats showed no changes in the fibre type proportion. Both the C + T and LP + T groups showed a higher percentage of fibres of type IIa, and a lower proportion of fibres of type IIb. In the soleus muscle, LP animals showed a reduction in the proportion of fibre types I and intermediate. C + T rats showed an increase in the fibre type I and IIa. In the LP + T rats, the proportions of the fibre types remained similar to control rats. CONCLUSIONS: Moderate physical training acts as a positive environmental stimulus that reverts the effects of a perinatal low-protein diet on the proportion of fibre types in skeletal muscle.

Maternal low-protein diet-induced delayed reflex ontogeny is attenuated by moderate physical training during gestation in rats.

We evaluated the effects of moderate- to low-intensity physical training during gestation on reflex ontogeny in neonate rats whose mothers were undernourished. Virgin female Wistar rats were divided into four groups as follows: untrained (NT, n 7); trained (T, n 7); untrained with a low-protein diet (NT+LP, n 7); trained with a low-protein diet (T+LP, n 4). Trained rats were subjected to a protocol of moderate physical training on a treadmill over a period of 4 weeks (5 d/week and 60 min/d, at 65 % of VO2max). After confirming the pregnancy, the intensity and duration of the exercise were reduced. Low-protein groups were provided with an 8 % casein diet, and controls were provided with a 17 % casein diet. Their respective offspring were evaluated (during the 10th-17th days of postnatal life) in terms of physical feature maturation, somatic growth and reflex ontogeny. Pups born to mothers provided with the low-protein diet during gestation and lactation showed delayed physical feature and reflex maturation and a deficit in somatic growth when compared with controls. However, most of these deficiencies were attenuated in pups of undernourished mothers undergoing training. In conclusion, physical training during gestation attenuates the effects of perinatal undernutrition on some patterns of maturation in the central nervous system during development.

Nutritional programming in the rat is linked to long-lasting changes in nutrient sensing and energy homeostasis in the hypothalamus.

BACKGROUND: Nutrient deficiency during perinatal development is associated with an increased risk to develop obesity, diabetes and hypertension in the adulthood. However, the molecular mechanisms underlying the developmental programming of the metabolic syndrome remain largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Given the essential role of the hypothalamus in the integration of nutritional, endocrine and neuronal cues, here we have analyzed the profile of the hypothalamus transcriptome in 180 days-old rats born to dams fed either a control (200 g/kg) or a low-protein (80 g/kg) diet through pregnancy and lactation. From a total of 26 209 examined genes, 688 were up-regulated and 309 down-regulated (P<0.003) by early protein restriction. Further bioinformatic analysis of the data revealed that perinatal protein restriction permanently alters the expression of two gene clusters regulating common cellular processes. The first one includes several gate keeper genes regulating insulin signaling and nutrient sensing. The second cluster encompasses a functional network of nuclear receptors and co-regulators of transcription involved in the detection and use of lipid nutrients as fuel which, in addition, link temporal and nutritional cues to metabolism through their tight interaction with the circadian clock. CONCLUSIONS/SIGNIFICANCE: Collectively, these results indicate that the programming of the hypothalamic circuits regulating energy homeostasis is a key step in the development of obesity associated with malnutrition in early life and provide a valuable resource for further investigating the role of the hypothalamus in the programming of the metabolic syndrome.

Perinatal undernutrition-induced obesity is independent of the developmental programming of feeding.

Protein or calorie restriction during gestation and/or suckling induces hyperphagia and increases the susceptibility to develop obesity, glucose intolerance and hypertension in adulthood. The mechanisms by which early nutrient restriction affects the normal physiological regulation of feeding as well as to what extent the metabolic programming of hyperphagia contributes to the long-term risk of obesity and insulin resistance remain, however, to be determined. Here the temporal pattern of food intake and the behavioural satiety sequence were investigated in the offspring of Sprague-Dawley rats fed a control (C) or a low-protein (LP) diet throughout pregnancy and lactation. During the first two months of their post-natal life, protein-restricted animals exhibited hyperphagia characterized by a delayed appearance of satiety, an increase in meal size and reduced latency to eat. Protein-restricted pups also exhibited an enhanced expression of the orexigenic peptides Agouti-related protein and neuropeptide Y and decreased hypothalamic levels of the anorexigenic peptide pro-opiomelanocortin. At 8 months, LP rats still consumed larger meals than their control counterparts but they ingested daily the same amount of food as control offspring and exhibited enhanced abdominal fat and increased levels of triglycerides and fatty acids in serum. These observations indicate that the hyperphagia observed in young LP rats results from a decreased action of negative feedback signals critical to meal termination and an enhanced function of the positive signals that initiate and maintain eating. These results also suggest that perinatal malnutrition programmes obesity through a mechanism independent of its effects on feeding behaviour.

Perinatal protein restriction reduces the inhibitory action of serotonin on food intake.

Early malnutrition has been associated with a high risk of developing obesity, diabetes and cardiovascular diseases in adulthood. In animals, poor perinatal nutrition produces hyperphagia and persistent increased levels of serotonin (5-HT) in the brain. Inasmuch as 5-HT is directly related to the negative regulation of food intake, here we have investigated whether the anorexic effects of 5-HT are altered by protein malnutrition. Pregnant Sprague-Dawley rats were fed ad libitum either a control (20% protein) or a low-protein (8% protein) diet throughout pregnancy and lactation. At weaning, pups received a standard diet and at 35 days their feeding behaviour was evaluated after the administration of DL-fenfluramine (DL-FEN), an anorexic compound that blocks the reuptake of 5-HT and stimulates its release. Male offspring born to protein-restricted dams exhibited significantly decreased body weight and hyperphagia compared with controls. DL-FEN dose-dependently reduced the 1 h chow intake at the onset of the dark cycle in both control and undernourished rats. However, the hypophagic effects of DL-FEN were significantly attenuated in animals submitted perinatally to protein restriction. The stimulatory action of DL-FEN on c-fos immunoreactivity within the paraventricular nucleus of the hypothalamus was also decreased in low-protein-fed rats. Further pharmacological analysis with selective 5-HT(1B) and 5-HT(2C) receptor agonist showed that the reduced anorexic effects of 5-HT in malnourished animals were coupled to a desensitization of 5-HT(1B) receptors. These observations indicate that the hyperphagia associated with metabolic programming is at least partially related to a reduced regulatory function of 5-HT on food intake.

A regional model (Northeastern Brazil) of induced mal-nutrition delays ontogeny of reflexes and locomotor activity in rats.

The aim of this study was to investigate the effects of malnutrition, induced by a regional basic diet (RBD), on motor development. RBD is a 7.87%-protein diet based on aliments typical of Northeastern Brazil, elaborated after nutritional investigation by Teodosio et al. (1979). Female rats were treated with RBD during lactation. The reflex ontogenesis and the development of locomotor activity in their offspring were assessed. Malnourished (MN) rats showed a delay in reflex maturation and in locomotor activity evolution. The decreased locomotor activity may be related to the reduced movement experiences induced by the delay in the reflex maturation. Occurring during the critical period of brain development, this fact could jeopardize all the steps in future locomotion evolution. The present results confirm deleterious effects of RDB-induced malnutrition on the somatic development and maturation of the nervous system (NS).