Developmental programming of adult hyperinsulinemia, increased proinflammatory cytokine production, and altered skeletal muscle expression of SLC2A4 (GLUT4) and uncoupling protein 3.
Fetal glucocorticoid excess programs detrimental effects in the adult phenotype including hyperleptinemia and aberrant glycemic control. In this study, we determined the interactive effects of maternal dexamethasone (Dex) treatment and postnatal dietary omega-3 (n-3) fatty acids on adult proinflammatory cytokine production and skeletal muscle expression of genes central to glucose handling and fatty acid metabolism. Dex acetate was administered to pregnant rats (0.75 microg/ml drinking water) from day 13 to term. Offspring of treated and control mothers were cross-fostered to mothers on either a standard (Std) or high n-3 (Hn3) diet, and remained on these diets postweaning. Adult offspring exposed to Dex in utero exhibited fasting hyperinsulinemia when raised on the Std diet but not when raised on the Hn3 diet. Dex also programmed increased plasma tumour necrosis factor alpha and interleukin 1 beta (IL-1 beta), but the increase in IL-1 beta was also prevented by the Hn3 diet. In skeletal muscle, expression of insulin regulated Slc2a4 (formerly known as GLUT4) was elevated (up to 15-fold) after Dex in utero, and this resulted in elevated intracellular, but not membrane-associated, SLC2A4 protein. Fetal glucocorticoid excess also reduced adult skeletal muscle Ucp3 expression in all offspring, whereas skeletal muscle expression of both Ppard and Ppargc1a were increased in females but not males. In conclusion, our data show that fetal glucocorticoid excess programs adult hyperinsulinemia and increased proinflammatory cytokine production. Related changes in the skeletal muscle Slc2a4, Ucp3, and Ppard indicate that fetal glucocorticoid excess disturbs adult glucose/fatty acid transport and metabolism.
Wyrwoll
Caitlin S
CS
School of Anatomy and Human Biology, The University of Western Australia, 35 Stirling Hwy, Crawley, Perth, Western Australia 6009, Australia.
Mark
Peter J
PJ
Mori
Trevor A
TA
Waddell
Brendan J
BJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D016207:Cytokines / Q000097:blood*; D003907:Dexamethasone / Q000494:pharmacology; D004041:Dietary Fats / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000235:genetics*; D006946:Hyperinsulinism / Q000097:blood* / Q000139:chemically induced / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007473:Ion Channels / Q000235:genetics*; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D024101:Mitochondrial Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D000071247:Uncoupling Protein 3
D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D016207:Cytokines; D004041:Dietary Fats; D015525:Fatty Acids, Omega-3; D051275:Glucose Transporter Type 4; D007328:Insulin; D053583:Interleukin-1beta; D015850:Interleukin-6; D007473:Ion Channels; D024101:Mitochondrial Proteins; C495694:Slc2a4 protein, rat; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C000604392:UCP3 protein, human; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D003907:Dexamethasone