|Hadsell, Darryl -|
|Olea, Walter -|
|Hadsell, Louise -|
Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: August 22, 2012
Publication Date: October 8, 2012
Citation: Hadsell, D.L., Olea, W., Hadsell, L.A. 2012. Maternal obesity in the agouti viable yellow (Avy) mouse produces defective secretory activation that is associated with mammary inflammation and activation of adrenocorticosteroid-dependent gene expression [abstract]. Proceedings of the International Milk Genomics Consortium: 9th International Symposium Milk Genomics and Human Health conference, October 8-10, 2012, Wageningen, The Netherlands. Technical Abstract: Maternal obesity is known to interfere with normal lactation in women, rodents, and dairy animals. Obesity is also correlated with profound changes in an array of endocrine factors and is causally linked with inflammation and insulin resistance. Recent work suggests that elevated aldosterone acting through mineralocorticoid receptor is responsible for M1 polarization of tissue macrophages leading to inflammation and insulin resistance during obesity. The A(vy) mouse is a monogenic model of obesity. The primary cause of obesity in this model is overexpression of the agouti gene, which produces hyperphagy. In characterizing this mouse as a model for maternal obesity and lactation, we first demonstrated that the weight-gain and survival of cross-foster litters suckling obese A(vy) dams was decreased. That the lactation defect was a specific consequence of maternal obesity was confirmed by comparing litter gain among obese A(vy) dams and A(vy) dams in which obesity was prevented by food-restriction. Histochemical analysis of macrophage markers demonstrated that maternal obesity was associated with increased numbers of mammary macrophages, an increase in the prevalence of crown-like structures, and an increase in the percentage of iNOS-positive macrophages. Analysis of mammary gene expression on day 1 and day 4 postpartum demonstrated increased mRNA levels of the inflammatory markers F4/80, Ccl2, ll6, and TNFalpha. In addition, mammary mRNA levels of Csn2, Lalba, and Cldn7 were diminished with maternal obesity. A micro-array analysis of mammary gene expression using the illumina whole genome mouse ref-6 array compared whole mammary tissue and laser-captured mammary epithelium from lean and obese dams on day 1 postpartum. Of the 45,281 probesets present on the array, 15,542 were detected above background (P<0.05). Of these, 233 genes differed (Benjamini-Hochberg-adjusted P<0.05) between lean and obese tissue and 57 differed between whole tissue and laser captured epithelium. As expected, the agouti (a) gene was elevated in tissue from obese dams. Using the Ingenuity Pathway Analysis software with the list of genes that were differentially affected by body composition demonstrated that the top scoring connectivity network had major nodes containing Nr3c1 and NfKB. Analysis of serum collected from lean and obese dams suggested that aldosterone was increased with obesity. In addition, the mammary expression of Edn1 and HSD11B1 were both increased with obesity. These results support the suggestion that inflammation and mammary corticosteroid signaling are major contributors to the secretory activation defect observed in obese A(vy) dams.