Maternal Obesity Promotes a Proinflammatory Signature in Rat Uterus and Blastocyst
- 23 August 2011
- journal article
- other
- Published by The Endocrine Society in Endocrinology
- Vol. 152 (11), 4158-4170
- https://doi.org/10.1210/en.2010-1078
Abstract
Maternal obesity at conception increases the risk of offspring obesity, thus propagating an intergenerational vicious cycle. Male offspring born to obese dams are hyperresponsive to high fat-diets, gaining greater body weight, fat mass, and additional metabolic sequelae compared to lean controls. In this report, we identify the impact of maternal obesity before conception, on the embryo, and intrauterine milieu during the periimplantation period. We conducted global transcriptomic profiling in the uterus and periimplantation blastocyst, gene/protein expression analyses of inflammatory pathways in conjunction with endocrine and metabolic characterization in the dams at implantation. Uterine gene expression profiles of lean and obese dams revealed distinct signatures for genes regulating inflammation and lipid metabolism. Both pathway and gene-set enrichment analysis revealed uterine nuclear factor-κB and c-Jun N-terminal kinase signaling to be up-regulated in the uterus of obese dams, which was confirmed via immunoblotting. Obese uteri also evidenced an inflammatory secretome with higher chemokine mRNA abundance (CCL2, CCL5, CCL7, and CxCL10) and related regulators (TLR2, CD14, and Ccr1). Increased inflammation in the uterus was associated with ectopic lipid accumulation and expression of lipid metabolic genes. Gene expression in sex-identified male periimplantation blastocyst at day postcoitum 4.5 was clearly influenced by maternal obesity (359 transcripts, ±1.4-fold), including changes in developmental and epigenetic regulators. Akin to the uterus, nuclear factor-κB-regulated proinflammatory genes (CCL4 and CCL5) increased and expression of antioxidant (GPx3) and mitochondrial (TFAM and NRF1) genes decreased in the obese embryos. Our results suggest that ectopic lipid and inflammation may link maternal obesity to increased predisposition of offspring to obesity later in life.Keywords
This publication has 58 references indexed in Scilit:
- Pregravid Obesity Associates With Increased Maternal Endotoxemia and Metabolic InflammationObesity, 2011
- Contrasting effects of different maternal diets on sexually dimorphic gene expression in the murine placentaProceedings of the National Academy of Sciences of the United States of America, 2010
- Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicityTrends in Endocrinology & Metabolism, 2010
- Sex determines the expression level of one third of the actively expressed genes in bovine blastocystsProceedings of the National Academy of Sciences of the United States of America, 2010
- A core gut microbiome in obese and lean twinsNature, 2008
- Methyl donor supplementation prevents transgenerational amplification of obesityInternational Journal of Obesity, 2008
- Adipocyte differentiation from the inside outNature Reviews Molecular Cell Biology, 2006
- Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substratesProceedings of the National Academy of Sciences of the United States of America, 2006
- Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistanceProceedings of the National Academy of Sciences of the United States of America, 2006
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005