Gestational restricted- and over-feeding promote maternal and offspring inflammatory responses that are distinct and dependent on diet in sheep†

Abstract

Inflammation may be a mechanism of maternal programming because it has the capacity to alter the maternal environment and can persist postnatally in offspring tissues. This study evaluated the effects of restricted- and over-feeding on maternal and offspring inflammatory gene expression using reverse transcription (RT)-PCR arrays. Pregnant ewes were fed 60% (Restricted), 100% (Control), or 140% (Over) of National Research Council requirements beginning on day 30.2 ± 0.2 of gestation. Maternal (n = 8-9 ewes per diet) circulating nonesterified fatty acid (NEFA) and expression of 84 inflammatory genes were evaluated at five stages during gestation. Offspring (n = 6 per diet per age) inflammatory gene expression was evaluated in the circulation and liver at day 135 of gestation and birth. Throughout gestation, circulating NEFA increased in Restricted mothers but not Over. Expression of different proinflammatory mediators increased in Over and Restricted mothers, but was diet-dependent. Maternal diet altered offspring systemic and hepatic expression of genes involved in chemotaxis at late gestation and cytokine production at birth, but the offspring response was distinct from the maternal. In the perinatal offspring, maternal nutrient restriction increased hepatic chemokine (CC motif) ligand 16 and tumor necrosis factor expression. Alternately, maternal overnutrition increased offspring systemic expression of factors induced by hypoxia, whereas expression of factors regulating hepatocyte proliferation and differentiation were altered in the liver. Maternal nutrient restriction and overnutrition may differentially predispose offspring to liver dysfunction through an altered hepatic inflammatory microenvironment that contributes to immune and metabolic disturbances postnatally.

Hyperglycemia-stimulating diet induces liver steatosis in sheep

“…Since overnutrition, hyperglycemia, insulin resistance and obesity are associated with systemic low-grade chronic inflammation [21][22][23][24] , we investigated the expression levels of several common inflammatory cytokines in circulating leukocytes. The hyperglycemic sheep fed the HC diet showed increased expression levels of the The HC diet induced significant hepatic steatosis and hepatomegaly.…”

Real supermodels wear wool: summarizing the impact of the pregnant sheep as an animal model for adaptive fetal programming

“…Although this model of maternal inflammation-induced IUGR, or MI-IUGR, produced milder fetal growth restriction than the hyperthermic PI-IUGR model, we found similar metabolic dysfunction and impaired muscle growth, as described in later sections. It should be noted that this model may be reflective of the chronic inflammatory conditions of maternal obesity (Yan et al, 2011a, 2011b; Ghnenis et al, 2017) and overeating (Jones et al, 2018), which produced both maternofetal inflammation and postnatal metabolic dysfunction.…”

“…In addition to mounting a chronically-sustained “adrenaline rush,” late-term fetuses also respond to hypoxemia with increased systemic inflammation (Jones et al, 2018). When IUGR was induced in fetal sheep by hypoxemia, circulating levels of the inflammatory cytokines TNFα and IL-6 as well as prostaglandins and activin A were elevated (Bertucci et al, 2011).…”

ASAS-SSR Triennnial Reproduction Symposium: Looking Back and Moving Forward—How Reproductive Physiology has Evolved: Fetal origins of impaired muscle growth and metabolic dysfunction: Lessons from the heat-stressed pregnant ewe1

“…In IUGR animal models, TNFα and IL-6 are elevated in late gestation (Bertucci et al, 2011), and we recently reported that maternofetal inflammation due to maternal bacterial endotoxin injection at mid-gestation in rats results in smaller fetuses with increased circulating TNFα at term, well after maternal biomarkers of inflammation had subsided (Cadaret et al, 2017a). Reduced delivery of nutrients can also increase fetal biomarkers of inflammation late in gestation (Jones et al, 2018). The adrenergic and inflammatory systems mediate many of the physiological changes affecting growth and metabolism in the IUGR fetus, and one prominent mode of action is inhibition of growth factors.…”