Glyphosate-based herbicide worsens alterations induced by cafeteria diet on rat uterus.

Exposure to glyphosate-based herbicides (GBH) and consumption of cafeteria (CAF) diet, which are widespread in Western society, seem to be associated with endometrial hyperplasia (EH). Here, we aimed to evaluate the effects of a subchronic low dose of a GBH added to CAF diet on the rat uterus. Female Wistar rats were fed from postnatal day (PND)21 until PND240 with chow (Control) or CAF diet. Since PND140, rats also received GBH (2 mg of glyphosate/kg/day) or water through food, yielding four experimental groups: Control, CAF, GBH and CAF+GBH. On PND240, CAF and CAF+GBH animals showed an increased adiposity index. Respect to Control group, no changes on the serum levels of 17ß-estradiol and progesterone were found. However, progesterone levels were higher in CAF+GBH group than in CAF and GBH groups. In the uterus, both studied factors alone and in combination induced morphological and molecular changes associated with EH. Furthermore, the addition of GBH provoked an increased thickness of subepithelial stroma in rats fed with CAF diet. As a consequence of GBH exposure, CAF+GBH rats exhibited an increased density of abnormal gland area, considered preneoplastic lesions, as well as a reduced PTEN and p27 expression, both tumor suppressor molecules that inhibit cell proliferation, respect to Control rats. These results indicate that the addition of GBH exacerbates the CAF-effects on uterine lesions and that the PTEN/p27 signaling pathway seems to be involved. Further studies focusing on the interaction between unhealthy diets and environmental chemicals should be encouraged to better understand uterine pathologies.

Depression: Monocytes on my mind.

Activation of the peripheral immune system contributes to stress-related neuropsychiatric symptoms. Recently in Nature, Cathomas et al. demonstrate that stress-induced social avoidance is mediated by monocyte-derived MMP8 that remodels the extracellular space of the nucleus accumbens.

Neonatal overfeeding alters the functioning of the mesolimbic dopaminergic circuitry involving changes in DNA methylation and effects on feeding behavior.

Mesolimbic dopaminergic circuit is essential for food reward and motivational behaviors and can contribute to weight gain and obesity. Litter reduction is a classical model for studying the effects of neonatal overfeeding and overweight. Litters of Wistar rats were reduced to 4 pups/dam for small litter (SL) and 10 pups/dam for normal litter at postnatal day (PND) 4. Immediately after performing the feeding behavior tests, the animals were sacrificed in PND21 and PND90. The ventral tegmental area (VTA), Nucleus Accumbens Core (NAcC) and Shell (NAcSh) were isolated from frozen brain sections using the Palkovits micropunch technique. RNA and DNA were extracted from these areas, gene expression was measured by RT-qPCR and DNA methylation levels were measured by MSRM-qPCR technique. SL-PND21 animals presented increased expression levels of Tyrosine Hydroxylase and Dopamine Receptor D2 in VTA, decreased expression levels of dopamine active transporter (DAT) in VTA, and higher expression levels of DAT in NAcC. On the other hand, SL-PND90 animals showed decreased expression levels of Dopamine Receptor D1 and higher expression of DAT in NAcSh. These animals also evidenced impaired sensory-specific satiety. In addition, altered promoter methylation was observed at weaning, and remained in adulthood. This work demonstrates that neonatal overfeeding induces disruptions in the mesolimbic dopaminergic circuitry and causes alterations in feeding behavior from weaning to adulthood, suggesting that the neonatal period is critical for the normal development of dopaminergic circuit that impact on feeding behavior.

Temporary effects of neonatal overfeeding on homeostatic control of food intake involve alterations in POMC promoter methylation in male rats.

A small litter (SL) model was used to determine how neonatal overfeeding affects the homeostatic control of food intake in male rats at weaning and postnatal day (PND) 90. At PND4, litters were reduced to small (4 pups/dam) or normal (10 pups/dam) litters. At weaning, SL rats showed higher body weight and characteristic features of the metabolic syndrome. Gene expression of pro-opiomelanocortin (POMC), cocaine and amphetamine regulated transcript, neuropeptide Y (NPY) and leptin and ghrelin (GHSR) receptors were increased and POMC promoter was hypomethylated in arcuate nucleus, indicating that the early development of obesity may involve the GHSR/NPY system and changes in POMC methylation state. At PND90, body weight, metabolic parameters and gene expression were restored; however, POMC methylation state remained altered. This work provides insight into the effects of neonatal overfeeding, showing the importance of developmental plasticity in restoring early changes in central pathways involved in metabolic programming.

IL-6R expressed on CNS vascular endothelial cells contributes to the development of experimental autoimmune encephalomyelitis in mice.

Experimental autoimmune encephalomyelitis (EAE) is the most common model for studying the molecular mechanisms of multiple sclerosis (MS). Here, we examined the CNS-restricted effects of classical interleukin (IL)-6 signaling on the development of EAE, using mice with cell-type specific deletion of the IL-6 receptor (IL-6R). We found that IL-6R deletion in CNS vascular endothelial cells, but not in microglia, ameliorated symptoms of EAE. The milder clinical symptoms in the gene-deleted mice were associated with less demyelination and immune cell infiltration/activation, and lower mRNA levels of the cytokines IL-17 and IL-1ß, as well as the cell adhesion molecules VCAM-1, ICAM-1 and ICAM-2 than what was seen in WT mice. These findings demonstrate that classical IL-6 signaling via endothelial cells of the CNS contributes substantially to the development of MS-like pathology, which should be taken into consideration when conceptualizing future therapeutic approaches.

Cafeteria diet induces progressive changes in hypothalamic mechanisms involved in food intake control at different feeding periods in female rats.

We studied the effects of cafeteria diet (CAF) intake from weaning on mRNA levels and DNA methylation state of feeding-related neuropeptides and hormone receptors in individual hypothalamic nuclei at different feeding periods. Four weeks of CAF (short-term) increased energy intake and adiposity, without affecting neuropeptides' expression. Eleven weeks of CAF (medium-term) increased energy intake, adiposity, leptinemia, and body weight, with an orexigenic response of the lateral hypothalamus, paraventricular and ventromedial nuclei, given by upregulation of Orexins, AgRP, and NPY opposed by an anorectic signal of the arcuate nucleus, which displayed a higher POMC expression. The changes in neuropeptidic mRNA levels were related to epigenetic modifications in their promoter regions. Metabolic and molecular changes were intensified after 20 weeks of diet (long-term). The alterations in these hypothalamic brain nuclei could add information about their differential role in food intake control, and how their action is disrupted during the development of obesity.

The impact of sensory and motor enrichment on the epigenetic control of steroidogenic-related genes in rat hippocampus.

In the present study, we analyzed the effects of a short-term environmental enrichment on the mRNA expression and DNA methylation of steroidogenic enzymes in the hippocampus. Thus, young adult (80-day-old) and middle-aged (350-day-old) Wistar female rats were exposed to sensory (SE) or motor (ME) enrichment during 10 days and compared to animals housed under standard conditions. SE was provided by an assortment of objects that included plastic tubes and toys; for ME, rodent wheels were provided. In young adult animals, SE and ME increased the mRNA expression of cytochrome P450 17α-hydroxylase/c17,20-lyase, steroid 5α-reductase type 1 (5αR-1) and 3α-hydroxysteroid dehydrogenase and decreased the methylation levels of 5αR-1 gene. In middle-aged rats, ME and SE upregulated the gene expression of aldosterone synthase and decreased the methylation state of its promoter. These results propose that SE and ME differentially regulate the transcription of neurosteroidogenic enzymes through epigenetic mechanisms in young and aged rats.

Induction of uterine hyperplasia after cafeteria diet exposure.

Our aim was to evaluate whether chronic administration of CAF affects the uterus and induces the morphological and molecular changes associated with endometrial hyperplasia. Female Wistar rats exposed to CAF from weaning for 20 weeks displayed increased energy intake, body weight and fat depots, but did not develop metabolic syndrome. The adult uteri showed an increase in glandular volume fraction and stromal area. The epithelial proliferation rate and protein expression of oestrogen receptor alpha (ERα) were also increased. The CAF diet enhanced leptin serum levels and the long form of leptin receptor (Ob-Rb) mRNA expression in the uterus. No changes were detected in either insulin serum levels or those of insulin growth factor I (IGF-I) mRNA expression. However the levels of IGF-I receptor (IGF-IR) mRNA were lower in CAF-fed animals. Overall, the results indicate that our rat model of the CAF diet produces morphological and molecular changes associated with uterine hyperplasia and could predispose to endometrial carcinogenesis.

Cafeteria diet differentially alters the expression of feeding-related genes through DNA methylation mechanisms in individual hypothalamic nuclei.

We evaluated the effect of cafeteria diet (CAF) on the mRNA levels and DNA methylation state of feeding-related neuropeptides, and neurosteroidogenic enzymes in discrete hypothalamic nuclei. Besides, the expression of steroid hormone receptors was analyzed. Female rats fed with CAF from weaning increased their energy intake, body weight, and fat depots, but did not develop metabolic syndrome. The increase in energy intake was related to an orexigenic signal of paraventricular (PVN) and ventromedial (VMN) nuclei, given principally by upregulation of AgRP and NPY. This was mildly counteracted by the arcuate nucleus, with decreased AgRP expression and increased POMC and kisspeptin expression. CAF altered the transcription of neurosteroidogenic enzymes in PVN and VMN, and epigenetic mechanisms associated with differential promoter methylation were involved. The changes observed in the hypothalamic nuclei studied could add information about their differential role in food intake control and how their action is disrupted in obesity.