Maternal nutrient restriction during pregnancy differentially alters the unfolded protein response in adipose and renal tissue of obese juvenile offspring

Abstract

Maternal diet during pregnancy can program an offspring's risk of disease in later life. Obesity adversely alters renal and adipose tissue function, resulting in chronic kidney disease and insulin resistance, respectively, the latter associated with dysregulation of the unfolded protein response (UPR). In view of the current obesity epidemic, we explored the combined effects of in utero early- to midgestational nutrient restriction and postnatal obesity on the UPR in ovine juvenile offspring. Nutrient restriction was coincident with fetal kidney development but prior to exponential adipose tissue deposition. Nutrient restricted (NR) and normal diet (control) offspring were exposed to an obesogenic environment throughout adolescence, resulting in similar degrees of juvenile obesity. NR offspring showed enhanced adipose tissue dysregulation characterized by activation of the UPR, perturbed insulin signaling, and marked inflammation, as demonstrated by increased abundance of crownlike structures and proinflammatory genes. Conversely, in renal tissue NR offspring had marked attenuation of cellular stress and inflammation evident as reduced activation of the UPR, down-regulation of proinflammatory genes, and less histological damage. In conclusion, obesity-related activation of the UPR can be determined by the in utero nutritional environment, demonstrating organ-specific effects dependent on the developmental phase targeted within the fetus.

The differential effects of the timing of maternal nutrient restriction in the ovine placenta on glucocorticoid sensitivity, uncoupling protein 2, peroxisome proliferator-activated receptor-γ and cell proliferation

“…Taken together, these findings indicate that if the level of food intake is kept constant through pregnancy and the mother is able to meet any energy deficit from mobilization of her own body reserves, placenta responses may not be required. However, an increase in fetal fat mass is seen in this group (Brennan et al 2005), that may be indicative of other adaptations within the placento-fetal unit that ultimately contribute to a marked change in adipose tissue function in later life, especially following obesity (Sharkey et al 2009). …”

“…Importantly, placental responses to maternal NR were coincident with the time of maximal placental growth (Ehrhardt & Bell 1995) and the beginning of the period exponential fetal growth. Such adaptations to NR may be beneficial for the survival of the fetus during a time of high metabolic demands but could alter the intrauterine environment to reset fetal organ growth and predisposing the offspring to metabolic disease in later life (McMillen & Robinson 2005, Sharkey et al 2009). The comparative importance of our findings is emphasized by the close similarity in the growth curves of the placenta and the fetus between sheep and humans.…”

“…These adaptations within the placenta are compensatory in nature, include a switch from proliferation to differentiation, and promote fatty acid metabolism. Despite the potential beneficial nature of these placental responses for fetal growth and development, they are likely to contribute to potentially adverse adaptations that would be detrimental to the long-term metabolic health of the offspring , Sharkey et al 2009). …”

Early programming of adipose tissue function: a large-animal perspective

“…The influence of a secondary 'insult' on ovine offspring who have experienced maternal nutrient restriction during early-mid gestation has been investigated by restricting offspring physical activity and providing ad libitum feed. From weaning to 1 year of age offspring from control and nutrient-restricted sheep were raised in an obesogenic environment that produces a 60% reduction in physical activity compared with pasturereared sheep (53,54) . At 1 year of age offspring that have experienced in utero nutrient restriction have a total body, subcutaneous and visceral fat weight similar to that of (49,52,54,59,63) .…”

“…From weaning to 1 year of age offspring from control and nutrient-restricted sheep were raised in an obesogenic environment that produces a 60% reduction in physical activity compared with pasturereared sheep (53,54) . At 1 year of age offspring that have experienced in utero nutrient restriction have a total body, subcutaneous and visceral fat weight similar to that of (49,52,54,59,63) . ›, Increased; fl, decreased; = , similar; NR, nutrient-restricted; ER, endoplasmic reticulum; IGF1, insulin-like growth factor 1.…”