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 (TNFα). TNFα contributes to adipocyte inflammation and impaired insulin signaling. TNFα 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 TNFα, TNFR1, and components of the UPR (Hspa5, ATF6, p-eIF2α, 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 TNFα, (2) increased mRNA levels of UPR components as well as p-eIF2a, and (3) impaired glucose tolerance after observed TNFα increased and after UPR activation. We speculate that programmed dysregulation of TNFα and UPR contributed to the development of glucose intolerance in male IUGR rats.

Background: Maternal tobacco smoke (MTS) predisposes human and rat offspring to visceral obesity in early adulthood. Glucocorticoid excess also causes visceral obesity. We hypothesized that in utero MTS would increase visceral adiposity and alter the glucocorticoid pathway in young adult rats. Methods:We developed a novel model of in utero MTS exposure in pregnant rats by exposing them to cigarette smoke from E11.5 to term. Neonatal rats were cross-fostered to control dams and weaned to standard rat chow through young adulthood (postnatal day 60). results: We demonstrated increased visceral adiposity (193%)*, increased visceral adipose 11-β hydroxysteroid dehydrogenase 1 mRNA (204%)*, increased serum corticosterone (147%)*, and no change in glucocorticoid receptor protein in adult male MTS rat offspring. Female rats exposed to MTS in utero demonstrated no change in visceral or subcutaneous adiposity, decreased serum corticosterone (60%)*, and decreased adipose glucocorticoid receptor protein (66%)*. *P < 0.05. conclusion: We conclude that in utero MTS exposure increased visceral adiposity and altered in the glucocorticoid pathway in a sex-specific manner. We speculate that in utero MTS exposure programs adipose dysfunction in adult male rat offspring via alteration in the glucocorticoid pathway.M aternal tobacco smoke (MTS) impacts more than 13% of pregnancies despite aggressive antismoking campaigns (1). In adult human studies, MTS exposure in utero predisposes to the development of metabolic syndrome, including increased visceral adiposity (2). The increased adiposity seen after gestating in an adverse intrauterine environment, such as maternal tobacco or nicotine exposure, is often adipose depot specific, with the visceral adipose tissue (VAT) increasing in excess to the subcutaneous adipose tissue (SAT) (3,4).VAT seems to have a detrimental role in the development of metabolic syndrome (5,6). Even when considering dietary and lifestyle choices, MTS exposure in utero independently increases the risk of developing visceral obesity (7,8). Children whose mothers smoked during pregnancy had decreased birth weights yet an increased obesity and BMI index as early as 9-10 y of age, independent of dietary intake and activity levels (8). Furthermore, the effect of MTS on body weight was stronger when mothers smoked during pregnancy compared with that of isolated smoke exposure in childhood (7). Taken together, these findings suggest that MTS exposure during this developmentally sensitive time period both causes intrauterine growth restriction (IUGR) and adversely programs obesity later in life.Little insight exists on how MTS programs increased visceral adiposity. Rodent studies examining the effect of in utero MTS exposure on the offspring have not examined the etiology of increased visceral adiposity. Rodent studies of tobacco smoke exposure only during lactation demonstrate increased adiposity (9). Furthermore, rodent studies of maternal nicotine, one of the many compounds found in tobacco smoke, demonstrate increa...