Maternal forced swimming reduces cell proliferation in the postnatal dentate gyrus of mouse offspring

Physical exercise positively affects the metabolism and induces proliferation of precursor cells in the adult brain. Maternal exercise likewise provokes adaptations early in the offspring. Using a high-intensity swimming protocol that comprises forced swim training before and during pregnancy, we determined the effect of maternal swimming on the mouse offspring's neurogenesis. Our data demonstrate decreased proliferation in sublayers of the postnatal dentate gyrus in offspring of swimming mother at postnatal day (P) 8 accompanied with decreased survival of newly generated cells 4 weeks later. The reduction in cell numbers was predominantly seen in the hilus and molecular layer. At P35, the reduced amount of cells was also reflected by a decrease in the population of newly generated immature and mature neurons of the granule cell layer. Our data suggest that forced maternal swimming at high-intensity has a negative effect on the neurogenic niche development in postnatal offspring

Exercise During Pregnancy Protects Adult Mouse Offspring From Diet-induced Obesity

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Background: Physical exercise induces positive alterations in gene expression involved in the metabolism of obesity. Maternal exercise provokes adaptations soon after birth in the offspring. Here, we investigated whether adult mouse offspring of swim-trained mothers is protected against the development of the deleterious effects of high fat diet (HFD). Methods: Our study comprises two parts. First, female C57BL/6 mice were divided into one sedentary and one swim-trained group (before and during pregnancy, n = 18). In the second part, adult offspring (n = 12) of trained and sedentary mothers was challenged to HFD for 16 weeks. Notably, most of the analysis was done in male offspring. Results: Our results demonstrate that maternal exercise has several beneficial effects on the mouse offspring and protects them from the deleterious effects of HFD in the adult. Specifically, swimming during pregnancy leads to lower birth weight in offspring through 2 months of age. When subjected to HFD for 4 month in the adulthood, our study presents novel data on the male offspring's metabolism of trained mothers. The offspring gained less weight, which was accompanied by less body fat, and they used more calories during daytime compared with offspring of sedentary mothers. Furthermore, we observed increased adiponectin expression in skeletal muscle, which was accompanied by decreased leptin levels and increased insulin sensitivity. Decreased interleukin-6 expression and increased peptide PYY levels were observed in sera of adult offspring of mothers that swam during pregnancy. Conclusions: Our results point to the conclusion that maternal exercise is beneficial to protect the offspring from developing obesity, which could be important for succeeding generations as well.12Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2013/04757-9

Ghrelin-induced Food Intake, but not GH Secretion, Requires the Expression of the GH Receptor in the Brain of Male Mice

Ghrelin stimulates both GH secretion and food intake. The orexigenic action of ghrelin is mainly mediated by neurons that coexpress agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH). GH also stimulates food intake and, importantly, ARHAgRP/NPY neurons express GH receptor (GHR). Thus, ghrelin-induced GH secretion may contribute to the orexigenic effect of ghrelin. Here, we investigated the response to ghrelin in male mice carrying GHR ablation specifically in neurons (brain GHR knockout [KO] mice) or exclusively in ARHAgRP/NPY neurons (AgRP GHR KO mice). Although brain GHR KO mice showed normal ghrelin-induced increase in plasma GH levels, these mutants lacked the expected orexigenic response to ghrelin. Additionally, brain GHR KO mice displayed reduced hypothalamic levels of Npy and Ghsr mRNA and did not elicit ghrelin-induced c-Fos expression in the ARH. Furthermore, brain GHR KO mice exhibited a prominent reduction in AgRP fiber density in the ARH and paraventricular nucleus of the hypothalamus (PVH). In contrast, AgRP GHR KO mice showed no changes in the hypothalamic Npy and Ghsr mRNAs and conserved ghrelin-induced food intake and c-Fos expression in the ARH. AgRP GHR KO mice displayed a reduced AgRP fiber density (∼16%) in the PVH, but this reduction was less than that observed in brain GHR KO mice (∼61%). Our findings indicate that GHR signaling in the brain is required for the orexigenic effect of ghrelin, independently of GH action on ARHAgRP/NPY neurons.Fil: Wasinski, Frederick. Universidade de Sao Paulo; BrasilFil: Barrile, Franco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Pedroso, João A. B.. Universidade de Sao Paulo; BrasilFil: Quaresma, Paula G. F.. Universidade de Sao Paulo; BrasilFil: Dos Santos, Willian O.. Universidade de Sao Paulo; BrasilFil: List, Edward O.. Ohio University; Estados UnidosFil: Kopchick, John J.. Ohio University; Estados UnidosFil: Perelló, Mario. Multidisciplinary Institute Of Cell Biology; ArgentinaFil: Donato, Jose. Universidade de Sao Paulo; Brasi

Exercise and Caloric Restriction Alter the Immune System of Mice Submitted to a High-Fat Diet

As the size of adipocytes increases during obesity, the establishment of resident immune cells in adipose tissue becomes an important source of proinflammatory mediators. Exercise and caloric restriction are two important, nonpharmacological tools against body mass increase. To date, their effects on the immune cells of adipose tissue in obese organisms, specifically when a high-fat diet is consumed, have been poorly investigated. Thus, after consuming a high-fat diet, mice were submitted to chronic swimming training or a 30% caloric restriction in order to investigate the effects of both interventions on resident immune cells in adipose tissue. These strategies were able to reduce body mass and resulted in changes in the number of resident immune cells in the adipose tissue and levels of cytokines/chemokines in serum. While exercise increased the number of NK cells in adipose tissue and serum levels of IL-6 and RANTES, caloric restriction increased the CD4+/CD8+ cell ratio and MCP-1 levels. Together, these data demonstrated that exercise and caloric restriction modulate resident immune cells in adipose tissues differently in spite of an equivalent body weight reduction. Additionally, the results also reinforce the idea that a combination of both strategies is better than either individually for combating obesity.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, BrazilUniv São Paulo, Sch Arts Sci & Humanities, BR-03828000 São Paulo, BrazilUniv São Paulo, Inst Biomed Sci, Lab Transplantat Immunobiol, Dept Immunol, BR-05508900 São Paulo, BrazilUniv Fed Pelotas, Sch Nutr, Dept Nutr, BR-96010610 Pelotas, RS, BrazilUniversidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, BrazilFAPESP: 2011/03528-0Web of Scienc

Changes in Glucose and Glutamine Lymphocyte Metabolisms Induced by Type I Interferon α

In lymphocytes (LY), the well-documented antiproliferative effects of IFN-α are associated with inhibition of protein synthesis, decreased amino acid incorporation, and cell cycle arrest. However, the effects of this cytokine on the metabolism of glucose and glutamine in these cells have not been well investigated. Thus, mesenteric and spleen LY of male Wistar rats were cultured in the presence or absence of IFN-α, and the changes on glucose and glutamine metabolisms were investigated. The reduced proliferation of mesenteric LY was accompanied by a reduction in glucose total consumption (35%), aerobic glucose metabolism (55%), maximal activity of glucose-6-phosphate dehydrogenase (49%), citrate synthase activity (34%), total glutamine consumption (30%), aerobic glutamine consumption (20.3%) and glutaminase activity (56%). In LY isolated from spleen, IFNα also reduced the proliferation and impaired metabolism. These data demonstrate that in LY, the antiproliferative effects of IFNα are associated with a reduction in glucose and glutamine metabolisms

Exercise during pregnancy protects adult mouse offspring from diet-induced obesity

Physical exercise induces positive alterations in gene expression involved in the metabolism of obesity. Maternal exercise provokes adaptations soon after birth in the offspring. Here, we investigated whether adult mouse offspring of swim-trained mothers is protected against the development of the deleterious effects of high fat diet (HFD). Our study comprises two parts. First, female C57BL/6 mice were divided into one sedentary and one swim-trained group (before and during pregnancy, n = 18). In the second part, adult offspring (n = 12) of trained and sedentary mothers was challenged to HFD for 16 weeks. Notably, most of the analysis was done in male offspring. Our results demonstrate that maternal exercise has several beneficial effects on the mouse offspring and protects them from the deleterious effects of HFD in the adult. Specifically, swimming during pregnancy leads to lower birth weight in offspring through 2 months of age. When subjected to HFD for 4 month in the adulthood, our study presents novel data on the male offspring’s metabolism of trained mothers. The offspring gained less weight, which was accompanied by less body fat, and they used more calories during daytime compared with offspring of sedentary mothers. Furthermore, we observed increased adiponectin expression in skeletal muscle, which was accompanied by decreased leptin levels and increased insulin sensitivity. Decreased interleukin-6 expression and increased peptide PYY levels were observed in sera of adult offspring of mothers that swam during pregnancy. Our results point to the conclusion that maternal exercise is beneficial to protect the offspring from developing obesity, which could be important for succeeding generations as well12FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2013/04757-

Caloric Restriction Is More Efficient than Physical Exercise to Protect from Cisplatin Nephrotoxicity via PPAR-Alpha Activation

The antineoplastic drug cisplatin promotes renal injury, which limits its use. Protocols that reduce renal cisplatin toxicity will allow higher doses to be used in cisplatin treatment. Here, we compare physical exercise and caloric restriction (CR) as protocols to reduce cisplatin renal injury in mice. Male C57BL/6 were divided into four groups: Control, cisplatin, exercise + cisplatin, and 30% CR + cisplatin. Animals were injected with a single dose of cisplatin (20 mg/kg i.p.) and sacrificed 96 h after injection. Quantitative real time PCR, histological analyses, immunohistochemistry, and biochemical measurements were performed to investigate renal injury, necrosis, apoptosis, and inflammatory mechanisms. Both protocols protected against cisplatin renal injury, but CR was more effective in reducing uraemia and renal necrosis. The CR + Cisplatin group exhibited reduced serum IL-1 beta and INF-alpha levels. No differences were noted in the renal mRNA expression of cytokines. Both interventions reduced apoptosis, but only the CR + Cisplatin group decreased TNFR2 protein expression. PPAR-ci was activated in mice after CR. An antagonist of PPAR-alpha blocked the protective effect of CR. Both interventions attenuated the nephrotoxicity caused by cisplatin injection, but CR + Cisplatin showed a better response by modulating TNFR2. Moreover, part of the CR benefit depends on PPAR-alpha activation.FAPESP (Fundacao de Apoio a Pesquisa do Estado de Sao Paulo)CAPES/DAADUniv Fed Sao Paulo, Dept Biofis, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Med, Disciplina Nefrol, Sao Paulo, BrazilUniv Sao Paulo, Inst Ciencias Biomed, Dept Immunol, Sao Paulo, BrazilUniv Sao Paulo, Dept Clin Med, Sao Paulo, BrazilUniv Fed Pelotas, Escola Nutr, Dept Nutr, Pelotas, BrazilMax Delbruck Ctr Mol Med, Berlin, GermanyUniv Fed Sao Paulo, Dept Biofis, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Med, Disciplina Nefrol, Sao Paulo, BrazilFAPESP: 2013/06207-6FAPESP: 2015/20082-7CAPES/DAAD: 427/15Web of Scienc

Carbamazepine inhibits angiotensin I-converting enzyme, linking it to the pathogenesis of temporal lobe epilepsy

We find that a common mutation that increases angiotensin I-converting enzyme activity occurs with higher frequency in male patients suffering from refractory temporal lobe epilepsy. However, in their brains, the activity of the enzyme is downregulated. As an explanation, we surprisingly find that carbamazepine, commonly used to treat epilepsy, is an inhibitor of the enzyme, thus providing a direct link between epilepsy and the renin-angiotensin and kallikrein-kinin systems. Translational Psychiatry (2012) 2, e93; doi:10.1038/tp.2012.21; published online 13 March 2012INNTConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Biophys, BR-04023032 São Paulo, BrazilUniversidade Federal de São Paulo, BR-04023032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pathol, BR-04023032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Neurol & Neurosurg, BR-04023032 São Paulo, BrazilUniv São Paulo, Sch Arts Sci & Humanities, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Sci & Technol, BR-04023032 São Paulo, BrazilNove de Julho Univ UNINOVE, Dept Rehabil Sci, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, BR-04023032 São Paulo, BrazilUniversidade Federal de São Paulo, BR-04023032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pathol, BR-04023032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Neurol & Neurosurg, BR-04023032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Sci & Technol, BR-04023032 São Paulo, BrazilWeb of Scienc