Diet-induced maternal obesity alters insulin signalling in male mice offspring rechallenged with a high-fat diet in adulthood

Modern lifestyle has resulted in an increase in the prevalence of obesity and its comorbidities in pregnant women and the young population. It has been well established that the consumption of a high-fat diet (HFD) has many direct effects on glucose metab118122FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO2011/22156-7; 2013/12003-

Maternal obesity during gestation and/or lactation : impact on lipid metabolism and HFD sensibility in offspring

Orientadores: Adriana Souza Torsoni, Marciane MilanskiDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências AplicadasResumo: O estado nutricional no início da vida está criticamente envolvido no fenótipo metabólico da prole na idade adulta. No entanto, as mudanças provocadas pelo consumo materno de dieta rica em gordura (DH) no período pré ou pós-natal devem ser melhor exploradas. No presente trabalho, avaliamos a contribuição do consumo de DH materna durante a gestação e lactação sobre os danos no metabolismo lipídico hepático da prole. Além disso, investigamos se a supernutrição precoce é capaz de programar a prole a uma resposta mais prejudicial à DH na vida adulta. No dia do nascimento (d0), a prole de mães obesas apresentou uma diminuição na expressão de Cpt1a e Acadvl, aumento na expressão de Agpat e Gpam, e menor conteúdo de miR-122 no fígado. Para confirmar a hipótese de que o período gestacional, por si só, poderia alterar o metabolismo lipídico da prole, foi utilizado o modelo de crossfostering. A prole gerada por mãe obesa, que foi amamentada por mãe controle, apresentou aumento no peso corporal e aumento da expressão de Agpat e Gpam no d28 em comparação com a prole de mãe controle que foi amamentada por mãe obesa. Na vida adulta (d82), a reintrodução de DH resultou em maior ganho de peso e maior teor de lipídio hepático na prole de mães obesas. Estes efeitos foram acompanhados por um desbalanço no metabolismo lipídico, demonstrado pela redução da expressão de Cpt1a e Acadvl e aumento na expressão de Agpat e Gpam, associados à menor expressão de miR-122 no fígado e menor conteúdo de p-HSL no tecido adiposo . Nossos dados sugerem que o consumo materno de DH durante a gestação leva à diminuição da expressão de miR-122 na prole, resultando em alterações metabólicas no início da vida que podem alterar permanentemente a homeostase lipídica e aumentar significativamente a susceptibilidade à obesidade e acúmulo ectópico de lipídios na vida adultaAbstract: Nutritional status in early life is critically involved in the metabolic phenotype of offspring in adulthood. However the changes triggered by maternal consumption of high-fat diet (HFD) in pre- or postnatal period should be better set out. Here we evaluated the contribution of maternal HFD consumption during gestation and lactation on hepatic lipid metabolism damages observed in the offspring. Moreover we investigate whether early overnutrition program offspring to harmful response to HFD in adult life. In the delivery day (d0) pups of obese dams showed a decrease in Cpt1a and ACADVL expression, increase in Agpat and Gpam expression, and lower miR-122 content in the liver. To confirm the hypothesis that the gestational period, by itself, could alter lipid metabolism, we used cross-fostered model. Pups fostered to chow dams presented an increase in body weight and higher Agpat and Gpam expression on d28 compared to pups fostered to HFD dams. In adult life (d82), the reintroduction of HFD resulted in higher body weight gain and hepatic lipid content in offspring from obese dams. These effects were accompanied by impaired in lipid metabolism, demonstrated by reduced Cpt1a and Acadvl and increased Agpat and Gpam expression associated with lower expression of miR-122 in liver and lower p-HSL in WAT. Our data suggests that maternal HFD consumption during gestational period leads to a decreased expression of miR-122 in the offspring resulting in metabolic changes in early life that can permanently alter lipid homeostasis and significantly increase susceptibility to obesity and ectopic lipid accumulationMestradoMetabolismo e Biologia MolecularMestra em Ciências da Nutrição e do Esporte e Metabolism

Autophagy proteins are modulated in the liver and hypothalamus of the offspring of mice with diet-induced obesity

2011/51.205-6Nutritional excess during pregnancy and lactation has a negative impact on offspring phenotype. In adulthood, obesity and lipid overload represent factorsthat compromise autophagy, a process of lysosomal degradation. Despite knowledge of the impact of obe343041FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO2011/51.205-62011/51.205-

Mathematical Models Including microRNA Levels of Mesenteric Adipose Tissue May Predict Postoperative Relapse in Crohn’s Disease Patients

Background and Aims: Recent evidence suggests that the mesenteric adipose tissue (MAT) near the affected intestine may play a role in Crohn's disease (CD) pathophysiology. Modulation of several transcripts has already been identified in the MAT of CD in the literature. Therefore, our aim was to validate the microRNA (miRNA) transcript levels and their target genes in the MAT of active CD patients and correlate them with clinical and epidemiological data. Methods: Samples from the MAT of surgical specimens from 25 active CD patients were obtained. The control group comprised fifteen patients who underwent surgery for other diseases, except inflammatory bowel diseases. Transcriptional levels of miRNA and their target genes were assessed by quantitative real-time polymerase chain reaction. The correlation between transcripts and clinical characteristics was obtained using multiple linear regression. The mathematical models (M) underwent a statistical filter to ensure robustness and reliability (P value .99; correct predictions of more than 60%). Results: miRNA-650 and miRNA-29c were upregulated in the MAT of CD compared to the control group (P < .0001 and P = .0032, respectively), besides presenting decreased levels of their target genes. Two were target genes of the miRNA-650: glutamine-fructose-6-phosphate transaminase 2 (P = .012) and aldehyde dehydrogenase 4 family (P = .0035); and 4 were targets of the miRNA-29c: cell death-inducing DFFA-like effector c (P = .001), E2F transcription factor-1 (P = .007), hypoxia-inducible factor 3 subunit alpha (P = .0029), and pyruvate dehydrogenase kinase 4 (P = .0054). We found 2 M with statistical strength and robustness. The performance test identified one model with 100% accuracy for predicting the month of recurrence and determining patients with less risk of early relapse after surgery. Conclusion: We demonstrate that miRNA-650 and miRNA-29c and some of their target genes, besides clinical and epidemiological variables, may be useful in a model to predict when disease relapse may occur in CD patients who underwent surgery. These findings constitute a potential tool to guide postoperative clinical management

Additional file 2: Figure S2. of Lipid overload during gestation and lactation can independently alter lipid homeostasis in offspring and promote metabolic impairment after new challenge to high-fat diet

Characterization of d42 offspring from control and obese dams prior to HFD exposure. Body weight (A), adiposity (B), caloric intake (C), fasting glucose (D), serum insulin (E) and lipids (CHOL and TAG - F), in d42 CC and HH groups. Values are means (n = 4-8) + - SEM. Student's t-test was used in all analyses to compare CC and HH groups. Different letters indicate statistical significance between groups (p ≤ 0.05). (JPG 390 kb

PEPCK content in liver and soleus.

<p>Western blot analysis of PEPCK in liver at d28 (A) and d82 (C), in soleus at d28 (B) and d82 (D). For control of gel loading, membranes were reblotted with β-actin or α-tubulin. Data are means ± SEM (n = 3–8). Two-way ANOVA (C and D) or t test (A and B) was used. In all blots, at least three different litters were considered. Different letters indicate significant differences at p<0.05.</p

Inflammatory and insulin signalling proteins in hypothalamus at d82.

<p>Western blot analysis of p-JNK (A), p-IKK (B), PTP1B (C), p-IRS1 (D) and p-AKT (E) in the hypothalamus at d82. For control of gel loading, membranes were reblotted with β-actin or total proteins. Data are means ± SEM (n = 3–8). Two-way ANOVA was used. In all blots, at least three different litters were considered. Different letters indicate significant differences at p<0.05.</p

Additional file 1: Figure S1. of Lipid overload during gestation and lactation can independently alter lipid homeostasis in offspring and promote metabolic impairment after new challenge to high-fat diet

Antropometric and biochemical parameters of dams at gestation and lactation. Body weight (A), adiposity (B), fasting glucose (C), serum insulin (D) and lipids (CHOL and TAG - E) and total hepatic lipid content (F) of control (C-D) and HFD (HF-D) dams in the gestational day 12, and lactational day 15. Values are means (n = 3-6) + - SEM. Student's t-test was used in all analyses to compare C-D and HF-D groups in each period (gestation or lactation). Different letters indicate statistical significance between groups (p ≤ 0.05). (JPG 667 kb

Antibodies used in Western Blot analysis.

<p>Antibodies used in Western Blot analysis.</p