Patrícia Rodrigues Lourenço Gomes

Maternal Melatonin Programs the Daily Pattern of Energy Metabolism in Adult Offspring

Background Shift work was recently described as a factor that increases the risk of Type 2 diabetes mellitus. In addition, rats born to mothers subjected to a phase shift throughout pregnancy are glucose intolerant. However, the mechanism by which a phase shift transmits metabolic information to the offspring has not been determined. Among several endocrine secretions, phase shifts in the light/dark cycle were described as altering the circadian profile of melatonin production by the pineal gland. The present study addresses the importance of maternal melatonin for the metabolic programming of the offspring. Methodology/Principal Findings Female Wistar rats were submitted to SHAM surgery or pinealectomy (PINX). The PINX rats were divided into two groups and received either melatonin (PM) or vehicle. The SHAM, the PINX vehicle and the PM females were housed with male Wistar rats. Rats were allowed to mate and after weaning, the male and female offspring were subjected to a glucose tolerance test (GTT), a pyruvate tolerance test (PTT) and an insulin tolerance test (ITT). Pancreatic islets were isolated for insulin secretion, and insulin signaling was assessed in the liver and in the skeletal muscle by western blots. We found that male and female rats born to PINX mothers display glucose intolerance at the end of the light phase of the light/dark cycle, but not at the beginning. We further demonstrate that impaired glucose-stimulated insulin secretion and hepatic insulin resistance are mechanisms that may contribute to glucose intolerance in the offspring of PINX mothers. The metabolic programming described here occurs due to an absence of maternal melatonin because the offspring born to PINX mothers treated with melatonin were not glucose intolerant. Conclusions/Significance The present results support the novel concept that maternal melatonin is responsible for the programming of the daily pattern of energy metabolism in their offspring.

Long-term disruption of maternal glucose homeostasis induced by prenatal glucocorticoid treatment correlates with miR-29 upregulation.

Excess of glucocorticoids (GCs) during pregnancy is strongly associated with the programming of glucose intolerance in the offspring. However, the impact of high GC levels on maternal metabolism is not clearly documented. This study aimed to test the hypothesis that mothers exposed to elevated levels of GCs might also display long-term disturbances in glucose homeostasis. Dexamethasone (DEX) was administered noninvasively to the mothers via drinking water between the 14th and the 19th days of pregnancy. Mothers were subjected to glucose and insulin tolerance tests at 1, 2, 3, 6, and 12 mo postweaning. Pregnant rats not treated with DEX and age-matched virgin rats were used as controls. Pancreatic islets were isolated at the 20th day of pregnancy and 12 mo postweaning in order to evaluate glucose-stimulated insulin secretion. The expression of the miR-29 family was also studied due to its responsiveness to GCs and its well-documented role in the regulation of pancreatic β-cell function. Rats treated with DEX during pregnancy presented long-term glucose intolerance and impaired insulin secretion. These changes correlated with 1) increased expression of miR-29 and its regulator p53, 2) reduced expression of syntaxin-1a, a direct target of miR-29, and 3) altered expression of genes related to cellular senescence. Our data demonstrate that the use of DEX during pregnancy results in deleterious outcomes to the maternal metabolism, hallmarked by reduced insulin secretion and glucose intolerance. This maternal metabolic programming might be a consequence of time-sustained upregulation of miR-29s in maternal pancreatic islets.

Short-term changes in handgrip strength, body composition, and lymphedema induced by breast cancer surgery

PURPOSE This study investigated short-term changes in body composition, handgrip strength, and presence of lymphedema in women who underwent breast cancer surgery. METHODS Ninety-five women participated in a cross-sectional study, divided into two groups: Control (n=46), with healthy women, and Experimental (n=49), with women six months after breast cancer surgery. The Experimental Group was subdivided into right total mastectomy (RTM, n=15), left total mastectomy (LTM, n=11), right quadrant (RQ, n=13), and left quadrant (LQ, n=10). It was also redistributed among women with presence (n=10) or absence (n=39) of lymphedema. Presence of lymphedema, handgrip strength, and body composition were assessed. RESULTS Trunk lean mass and handgrip strength were decreased in the Experimental Group. Total lean mass was increased in the LTM compared to RTM or LQ. Left handgrip strength in LTM was decreased compared to RTM and RQ and in LQ compared to RTM and RQ. Finally, total lean mass, trunk fat mass, trunk lean mass, right and left arm lean mass were increased in women with lymphedema. CONCLUSIONS Breast cancer survivors have changes in their body composition and in handgrip strength six months after surgery; however, the interaction between the type of surgery and its impact is unclear. Furthermore, women who developed lymphedema in this period showed more significant changes in the body composition, but they were not enough to cause impairment in handgrip strength.

Selective regulation of hepatic lipid metabolism by the AMP-activated protein kinase pathway in late-pregnant rats

The liver plays an essential role in maternal metabolic adaptation during late pregnancy. With regard to lipid metabolism, increased secretion of very low-density lipoprotein (VLDL) is characteristic of late pregnancy. Despite this well-described metabolic plasticity, the molecular changes underlying the hepatic adaptation to pregnancy remain unclear. As AMPK is a key intracellular energy sensor, we investigated whether this protein assumes a causal role in the hepatic adaptation to pregnancy. Pregnant Wistar rats were treated with vehicle or AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) for 5 days starting at gestational day 14. At the end of treatment, the rats were subjected to an intraperitoneal pyruvate tolerance test and in situ liver perfusion with pyruvate. The livers were processed for Western blot analysis, quantitative PCR, thin-layer chromatography, enzymatic activity, and glycogen content measurements. Blood biochemical profiles were also assessed. We found that AMPK and ACC phosphorylation were reduced in the livers of pregnant rats in parallel with a reduced level of hepatic gluconeogenesis of pyruvate. This effect was accompanied by both a reduction in the levels of hepatic triglycerides (TG) and an increase in circulating levels of TG. Treatment with AICAR restored hepatic levels of TG to those observed in nonpregnant rats. Additionally, AMPK activation reduced the upregulation of genes related to VLDL synthesis and secretion observed in the livers of pregnant rats. We conclude that the increased secretion of hepatic TG in late pregnancy is concurrent with a transcriptional profile that favors VLDL production. This transcriptional profile results from the reduction in hepatic AMPK activity.

Prolonged fasting elicits increased hepatic triglyceride accumulation in rats born to dexamethasone-treated mothers

We investigated the effect of dexamethasone during the last week of pregnancy on glucose and lipid metabolism in male offspring. Twelve-week old offspring were evaluated after fasting for 12-hours (physiological) and 60-hours (prolonged). Physiological fasting resulted in glucose intolerance, decreased glucose clearance after pyruvate load and increased PEPCK expression in rats born to dexamethasone-treated mothers (DEX). Prolonged fasting resulted in increased glucose tolerance and increased glucose clearance after pyruvate load in DEX. These modulations were accompanied by accumulation of hepatic triglycerides (TG). Sixty-hour fasted DEX also showed increased citrate synthase (CS) activity, ATP citrate lyase (ACLY) content, and pyruvate kinase 2 (pkm2), glucose transporter 1 (slc2a1) and lactate dehydrogenase-a (ldha) expressions. Hepatic AKT2 was increased in 60-hour fasted DEX, in parallel with reduced miRNAs targeting the AKT2 gene. Altogether, we show that metabolic programming by prenatal dexamethasone is characterized by an unexpected hepatic TG accumulation during prolonged fasting. The underlying mechanism may depend on increased hepatic glycolytic flux due to increased pkm2 expression and consequent conversion of pyruvate to non-esterified fatty acid synthesis due to increased CS activity and ACLY levels. Upregulation of AKT2 due to reduced miRNAs may serve as a permanent mechanism leading to increased pkm2 expression.

Dexamethasone Administration During Late Gestation Has No Major Impact on Lipid Metabolism, but Reduces Newborn Survival Rate in Wistar Rats

A rise in plasma triacylglycerol levels is a common physiological occurrence during late gestation and excess of glucocorticoids (GCs) has been shown to impair lipid metabolism. Based on those observations, we investigated whether the administration of dexamethasone during the late gestational period could exacerbate this pregnancy associated hypertriacylglycerolemia in rats. For this, female Wistar rats were treated with dexamethasone (0.2 mg/kg of body mass in the drinking water on days 14–19 of pregnancy; DP group) or equivalent days in the virgin rats (DV group). Untreated pregnant rats (control pregnant group) and age-matched virgin rats (control virgin group) were used as controls. Functional, biochemical, and molecular analyses were carried out after treatment with GC and in the control groups. Euthanasia was performed on day 20 of pregnancy. The metabolic parameters of the mothers (dams) at the time of weaning and 6 months later, as well as newborn survival, were evaluated. We observed that neither dexamethasone nor pregnancy affected blood glucose or glucose tolerance. Hypertriacylglycerolemia associated with lipid intolerance or reduced hepatic triacylglycerol clearance was observed during the late gestational period. GC treatment caused a further increase in basal plasma triacylglycerol levels, but did not have a significant effect on lipid tolerance and hepatic triacylglycerol clearance in pregnant rats. GC, but not pregnancy, caused few significant changes in mRNA expression of proteins involved in lipid metabolism. Dexamethasone during pregnancy had no impact on lipid metabolism later in the dams’ life; however, it led to intra-uterine growth restriction and reduced pup survival rate. In conclusion, GC exposure during the late gestational period in rats has no major impact on maternal lipid homeostasis, soon after parturition at weaning, or later in the dams’ life, but GC exposure is deleterious to the newborn when high doses are administered at late gestation. These data highlight the importance of performing an individualized and rigorous control of a GC treatment during late pregnancy considering its harmful impact on the fetuses’ health.

Qualidade de vida, depressão e dor em mulheres pós cirurgia de cancer de mama.

depressao, dor e consequente declinio na qualidade de vida (QV). Objetivo: Avaliar a QV, depressao e dor em mulheressubmetidas a intervencao cirurgica de câncer de mama. Metodo: Cento e trinta e duas mulheres foram divididas em tresgrupos: G1 (n=46), submetidas a tratamento cirurgico para câncer de mama que frequentavam um servico de fisioterapia;G2 (n=43), submetidas a tratamento cirurgico para câncer de mama que nao frequentavam um servico de fisioterapiae G3 (n=43), grupo controle sem diagnostico de câncer de mama. Inicialmente, as participantes foram submetidas aavaliacao fisica, para imparidades (edema de braco, limitacao de movimento articular do ombro e dor). Foi realizada umaavaliacao para deteccao de presenca e de nivel de depressao, por meio do Inventario de Depressao de Beck (BDI) e paraavaliacao da QV com aspectos relacionados a saude, foi utilizado o questionario SF-36. Resultados: foi evidenciada diminuicaoda mobilidade em todos os movimentos do ombro em ambos os grupos com intervencao cirurgica (G1 e G2). Ador e a prevalencia de linfedema tiveram relacao com a depressao, sendo mais evidente em G1. Quanto aos aspectos relacionadosa QV, o SF-36 demonstrou que o grupo G1 apresentou maiores escores nos dominios fisicos e emocionais emrelacao ao grupo G2, e os dois grupos apresentaram baixo escore no dominio dor. Houve presenca de depressao, quandoavaliada pelo BDI, em 35% das mulheres do grupo G1, 49% do grupo G2 e 28% do grupo G3. Ainda, o G1 mostra umafraca tendencia de pessoas em niveis mais proximos a depressao em relacao ao controle (G3). Conclusao: Pode-se concluirque a participacao em um programa de fisioterapia resultou em melhora da QV e que a depressao pode estar relacionadaaos niveis de dor no pos-operatorio de câncer de mama. Palavras-chave: Fisioterapia; Mastectomia; Dor; Qualidade de vida.AbstractIntroduction:

AVALIAÇÃO DO COMPLEXO DO OMBRO EM MULHERES SUBMETIDAS À INTERVENÇÃO CIRÚRGICA PARA TRATAMENTO DE CÂNCER DE MAMA

A cirurgia de câncer de mama esta associada, em torno de 70% dos casos, a complicacoes que podem levar a limitacao e diminuicao da mobilidade do ombro. Considerando as alteracoes decorrentes das cirurgias mamarias, o objetivo deste estudo foi realizar uma avaliacao fisica do ombro homolateral e contralateral a cirurgia, comparando os resultados obtidos nos dois ombros. Este estudo foi realizado com 21 mulheres submetidas a mastectomia ou quadrandectomia unilateral, incluidas, pelo menos ha seis meses, em um programa de reabilitacao em fisioterapia. Precedendo o inicio das avaliacoes clinicas, uma ficha de avaliacao especifica para esta populacao foi desenvolvida, identificando alteracoes agudas e cronicas. A idade media das pacientes foi 52,10 anos. De acordo com o exame fisico, a aderencia cicatricial estava presente em 14% das pacientes e o linfedema em 86% destas. Durante a palpacao, 95% das pacientes apresentaram dor e pontos-gatilho nos musculos trapezio, esternocleidomastoideo, escalenos e romboides. As medianas da amplitude de movimento do ombro homolateral e contralateral a cirurgia foram: flexao, 130o/154o; extensao, 38o/40o; rotacao lateral, 60o/85o; rotacao medial, 70o/90o e abducao 115o/145o. De acordo com os resultados, houve uma diminuicao significativa em todos os movimentos do ombro homolateral, quando comparado ao contralateral a cirurgia. Diante do exposto, pode-se concluir que a avaliacao, por meio da ficha especifica, elaborada para pacientes com câncer de mama, foi eficaz para identificar complicacoes pos-cirurgicas no ombro desta populacao. Portanto, esta avaliacao foi importante para identificar disfuncoes fisicas, visando a reabilitacao e independencia nas atividades de vida diaria destas mulheres.