Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1.
Obesity impairs reproductive functions through multiple mechanisms, possibly through disruption of ovarian function. We hypothesized that increased adiposity will lead to a proinflammatory gene signature and upregulation of Egr-1 protein in ovaries from obese (OB; n = 7) compared with lean (LN; n = 10) female Sprague-Dawley rats during the peri-implantation period at 4.5 days postcoitus (dpc). Obesity was induced by overfeeding (40% excess calories for 28 days) via total enteral nutrition prior to mating. OB dams had higher body weight (P < 0.001), greater fat mass (P < 0.001), and reduced lean mass (P < 0.05) and developed metabolic dysfunction with elevated serum lipids, insulin, leptin, and CCL2 (P < 0.05) compared with LN dams. Microarray analyses identified 284 differentially expressed genes between ovaries from LN vs. OB dams (±1.3 fold, P < 0.05). RT-qPCR confirmed a decrease in expression of glucose transporters GLUT4 and GLUT9 and elevation of proinflammatory genes, including CCL2, CXCL10, CXCL11, CCR2, CXCR1, and TNFα in ovaries from OB compared with LN (P < 0.05). Protein levels of PI3K and phosphorylated Akt were significantly decreased (P < 0.05), whereas nuclear levels of Egr-1 (P < 0.05) were increased in OB compared with LN ovaries. Moreover, Egr-1 was localized to granulosa cells, with the highest expression in cumulus cells of preovulatory follicles. mRNA expression of VCAN, AURKB, and PLAT (P < 0.05) correlated with %visceral fat weight (r = 0.51, -0.77, and -0.57, respectively, P ≤ 0.05), suggesting alterations in ovarian function with obesity. In summary, maternal obesity led to an upregulation of inflammatory genes and Egr-1 expression in peri-implantation ovarian tissue and a concurrent downregulation of GLUTs and Akt and PI3K protein levels.
Arkansas Children's Nutrition Center, Little Rock, Arkansas; Interdisciplinary Biomedical Sciences Program, University of Arkansas for Medical Sciences, Little Rock, Arkansas;
Meghan
M
Ruebel
Arkansas Children's Nutrition Center, Little Rock, Arkansas; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and.
Kartik
K
Shankar
Department of Veterinary Integrative Biosciences, Texas A & M University, College Station, Texas.
Dana
D
Gaddy
Arkansas Children's Nutrition Center, Little Rock, Arkansas;
Forrest
F
Lindsey
Arkansas Children's Nutrition Center, Little Rock, Arkansas; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and.
Thomas
T
Badger
Arkansas Children's Nutrition Center, Little Rock, Arkansas; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and AndresAline@uams.edu.
Aline
A
Andres
D000818:Animals; D064107:Aurora Kinase B / Q000235:genetics; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000235:genetics; D054357:Chemokine CXCL10 / Q000235:genetics; D054371:Chemokine CXCL11 / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D005260:Female; D051275:Glucose Transporter Type 4 / Q000235:genetics; D006107:Granulosa Cells / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010053:Ovary / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000235:genetics; D023062:Receptors, Interleukin-8A / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D010959:Tissue Plasminogen Activator / Q000235:genetics; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation; D053675:Versicans / Q000235:genetics
C491766:Ccl2 protein, rat; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; C091326:Cxcl10 protein, rat; C515205:Cxcl11 protein, rat; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; C498776:GLUT6 protein, rat; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D054390:Receptors, CCR2; D023062:Receptors, Interleukin-8A; C495694:Slc2a4 protein, rat; D014409:Tumor Necrosis Factor-alpha; D053675:Versicans; D019869:Phosphatidylinositol 3-Kinases; C576925:Aurkb protein, rat; D064107:Aurora Kinase B; D051057:Proto-Oncogene Proteins c-akt; D010959:Tissue Plasminogen Activator
early growth response factor 1; gene expression; inflammation; obesity; reproduction