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.

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.

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.

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.