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Effect of GLP-1 Receptor Activation on Offspring Kidney Health in a Rat Model of Maternal Obesity.

ABSTRACT: Maternal obesity is associated with an increased risk of chronic disease in offspring, including type 2 diabetes (T2D). Exendin-4 (Exd-4) activates the glucagon like peptide-1 (GLP-1) receptor thereby decreasing serum glucose levels and body weight. In addition, Exd-4 has been shown to reduce renal and cardiac complications in experimental models of T2D. We hypothesized that treatment with Exd-4 would ameliorate the detrimental effects of maternal and diet-induced obesity on renal characteristics in offspring. Female Sprague-Dawley rats were fed either normal or high-fat diet (HFD) for 6 weeks prior to pregnancy, during pregnancy and lactation, and their offspring were weaned to normal or HFD. The offspring were randomized to Exd-4 or placebo from weaning and their kidneys harvested at Week 9. We found that the kidneys of offspring from obese mothers, regardless of postnatal diet, had significantly increased markers of inflammation, oxidative stress and fibrosis. Exd-4 ameliorated the negative renal effects of maternal obesity and in particular, reduced renal inflammation, oxidative stress and fibrosis. In conclusion, maternal obesity has persisting effects on renal structure in the offspring. GLP-1 analogues are potentially useful for protecting against the deleterious effects of maternal obesity on renal physiology in offspring.

SUBMITTER: Glastras SJ

PROVIDER: S-EPMC4804207 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Effect of GLP-1 Receptor Activation on Offspring Kidney Health in a Rat Model of Maternal Obesity.

Glastras Sarah J SJ Chen Hui H McGrath Rachel T RT Zaky Amgad A AA Gill Anthony J AJ Pollock Carol A CA Saad Sonia S

Scientific reports 20160323

Maternal obesity is associated with an increased risk of chronic disease in offspring, including type 2 diabetes (T2D). Exendin-4 (Exd-4) activates the glucagon like peptide-1 (GLP-1) receptor thereby decreasing serum glucose levels and body weight. In addition, Exd-4 has been shown to reduce renal and cardiac complications in experimental models of T2D. We hypothesized that treatment with Exd-4 would ameliorate the detrimental effects of maternal and diet-induced obesity on renal characteristic ...[more]

PMID: 27004609

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Project description:ObjectiveObesity and cardiovascular disease are major global public health problems. Maternal obesity has been linked to multiple adverse health consequences for both mother and baby. Obesity during pregnancy may adversely alter the intrauterine environment, which has been hypothesised to predispose the offspring to poorer cardiovascular health throughout life. In this paper, we systematically review current literature examining the links between maternal obesity and offspring cardiovascular health.MethodsThis study is registered with PROSPERO (CRD42021278567) and was conducted in accordance with the PRISMA guidelines. A comprehensive systematic literature search was conducted, including two electronic databases (Ovid Medline, Embase), cross-referencing, author searching, and grey literature searches. We selected studies exploring the relationship between maternal obesity and offspring cardiovascular health, using pre-defined eligibility criteria. Studies were critically appraised using the ROBINS-I tool.ResultsFrom 1,214 results, 27 articles met the eligibility criteria. Multiple cardiovascular outcomes were considered, including congenital heart disease, cardiometabolic parameters, and cardiovascular diseases in neonates, children, and adults. In these studies, maternal obesity was consistently associated with congenital heart disease, several adverse cardiometabolic parameters throughout life including higher body mass index and insulin levels, and greater risk of cardiovascular disease in adulthood. Hypothesized underlying mechanisms are complex and multifactorial comprising genetic, environmental, and socioeconomic components, which can be difficult to quantify. Heterogeneity in study designs, highly selected study samples, and high risk of bias in some studies limit conclusions regarding causality.ConclusionsWe identified consistent evidence of links between maternal obesity and poorer offspring cardiovascular health throughout the lifecourse, extending from the neonatal period into adulthood. Although underlying mechanisms are unclear, our findings support consideration of targeted maternal obesity prevention for promotion of offspring cardiovascular health. This all-encompassing systematic review provides critical appraisal of the latest evidence, defines gaps and biases of existing literature, and may inform potential new public health strategies for cardiovascular disease prevention.Systematic review registration[https://www.crd.york.ac.uk/prospero], identifier PROSPERO (CRD42021278567).

Project description:The risk of obesity (OB) in adulthood is strongly influenced by maternal body composition. Here we examined the hypothesis that maternal OB influences white adipose tissue (WAT) transcriptome and increases propensity for adipogenesis in the offspring, prior to the development of OB, using an established model of long-term metabolic programming. Employing an overfeeding-based rat model, in which exposure to OB is limited to preconception and gestation alone, we conducted global transcriptomic profiling in WAT, and gene/protein expression analysis of lipogenic and adipogenic pathways and examined adipogenic differentiation of WAT stromal-vascular cells ex vivo. Using reduced representation bisulfite sequencing we also evaluated genome-scale changes in DNA methylation in offspring WAT. Maternal OB led to extensive changes in expression of genes (± 1.8-fold, P ? .05), revealing a distinct up-regulation of lipogenic pathways in WAT. mRNA expression of a battery of sterol regulatory element-binding protein-1-regulated genes was increased in OB-dam offspring, which were confirmed by immunoblotting. In conjunction with lipogenic gene expression, OB-dam offspring showed increased glucose transporter-4 mRNA/protein expression and greater AKT phosphorylation following acute insulin challenge, suggesting sensitization of insulin signaling in WAT. Offspring of OB dams also exhibited increased in vivo expression of adipogenic regulators (peroxisome proliferator-activated receptor-?, CCAAT enhancer binding protein ? [C/EBP-?] and C/EBP-?), associated with greater ex vivo differentiation of WAT stromal-vascular cells. These transcriptomic changes were associated with alterations in DNA methylation of CpG sites and CGI shores, proximal to developmentally important genes, including key pro-adipogenic factors (Zfp423 and C/EBP-?). Our findings strongly suggest that the maternal OB in utero alters adipocyte commitment and differentiation via epigenetic mechanisms.

Project description:Maternal high-fat diet consumption predisposes to metabolic and liver dysfunction in F1 male and female at young adulthood. Purpose: We used RNA-seq to determine the liver transcriptome of male and female F1 of MO and control fed mothers. Methods: Female Wistar rat mothers ate control (C) or obesogenic (MO) diet from the time they were weaned through breeding at postnatal day (PND) 120, delivery and lactation. After weaning all male and female F1 ate control diet. At PND 110 liver and fat were collected to analyze metabolites, histology and liver differentially expressed genes. To identify the functional F1 liver changes due to MO, we evaluated the differentially expressed genes (DEGs) between MO and C males and females with separate pairwise comparisons due to the marked differences between males and females. Genes were filtered based on ≥ 1.4 fold change (FC) and nominal P value <0.05 (Student´s t-test). Results: MOF1 males presented greater physiologic and histological NAFLD characteristics than MOF1 females. RNA-seq revealed 1,365 genes significantly changed in male MOF1 liver and only 70 genes in MOF1 female compared with controls. GO and KEGG analysis identified differentially expressed genes related to metabolic process. Male MOF1 liver showed the following altered pathways: insulin signaling (22 genes), phospholipase D signaling (14 genes), NAFLD (13 genes), and glycolysis/ gluconeogenesis (7 genes). In contrast, few genes were altered in these pathways in MOF1 females. Conclusions: These results improve understanding of the mechanism by which a maternal high fat diet affects their F1. In summary, MO programs sex-dependent F1 changes in insulin, glucose and lipid signaling pathways, leading to liver dysfunction and insulin resistance. Male adult MOF1 livers show global down-regulation of genes that are required for normal function of major liver metabolic pathways. This new knowledge is important for producing sex-specific interventions.

Dataset Information

Effect of GLP-1 Receptor Activation on Offspring Kidney Health in a Rat Model of Maternal Obesity.

Publications

Effect of GLP-1 Receptor Activation on Offspring Kidney Health in a Rat Model of Maternal Obesity.

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