title: Intrauterine growth restriction increases TNF α and activates the unfolded protein response in male rat pups.
abstract: Intrauterine growth restriction (IUGR) programs adult disease, including obesity and insulin resistance. Our group previously demonstrated that IUGR dysregulates adipose deposition in male, but not female, weanling rats. Dysregulated adipose deposition is often accompanied by the release of proinflammatory signaling molecules, such as tumor necrosis factor alpha (TNF α ). TNF α contributes to adipocyte inflammation and impaired insulin signaling. TNF α has also been implicated in the activation of the unfolded protein response (UPR), which impairs insulin signaling. We hypothesized that, in male rat pups, IUGR would increase TNF α , TNFR1, and components of the UPR (Hspa5, ATF6, p-eIF2 α , and Ddit3) prior to the onset of obesity. We further hypothesized that impaired glucose tolerance would occur after the onset of adipose dysfunction in male IUGR rats. To test this hypothesis, we used a well-characterized rat model of uteroplacental insufficiency-induced IUGR. Our primary findings are that, in male rats, IUGR (1) increased circulating and adipose TNF α , (2) increased mRNA levels of UPR components as well as p-eIF2a, and (3) impaired glucose tolerance after observed TNF α increased and after UPR activation. We speculate that programmed dysregulation of TNF α and UPR contributed to the development of glucose intolerance in male IUGR rats.
authors.affiliation: Division of Nutrition, University of Utah, Salt Lake City, UT 84158, USA.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Riddle
authors.affiliation: Division of Nutrition, University of Utah, Salt Lake City, UT 84158, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Campbell
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT 84158, USA.
authors.forename: Brook Y
authors.initials: BY
authors.lastname: Lang
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT 84158, USA.
authors.forename: Ryann
authors.initials: R
authors.lastname: Bierer
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT 84158, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Nutrition, University of Utah, Salt Lake City, UT 84158, USA.
authors.forename: Heidi N
authors.initials: HN
authors.lastname: Bagley
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT 84158, USA ; Division of Neonatology, University of Utah, P.O. Box 581289, Salt Lake City, UT 84158, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Joss-Moore
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D005317:Fetal Growth Retardation / Q000378:metabolism*; D018149:Glucose Intolerance / Q000209:etiology* / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D007328:Insulin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha