Maternofetal inflammation induced for 2 wk in late gestation reduced birth weight and impaired neonatal growth and skeletal muscle glucose metabolism in lambs

Abstract

Intrauterine stress impairs growth and metabolism in the fetus and offspring. We recently found that sustained maternofetal inflammation resulted in intrauterine growth restricted fetuses (MI-IUGR) with asymmetric body composition, impaired muscle glucose metabolism, and β-cell dysfunction near term. These fetuses also exhibited heightened inflammatory tone, which we postulated was a fetal programming mechanism for the IUGR phenotype. Thus, the objective of this study was to determine whether poor growth and metabolism persisted in MI-IUGR lambs after birth. Polypay ewes received serial lipopolysaccharide or saline injections in the first 2 wk of the 3 rd trimester of pregnancy to produce MI-IUGR (n = 13) and control (n = 12) lambs, respectively. Lambs were catheterized at 25 d of age. β cell function was assessed at 29 d, hindlimb glucose metabolism at 30 d, and daily blood parameters from d 26 to 31. Glucose metabolism was also assessed in flexor digitorum superficialis (FDS) muscle isolated at necropsy on d 31. Asymmetric body composition persisted in MI-IUGR neonates, as these lambs were lighter (P < 0.05) than controls at birth and 31 d, but body and cannon bone lengths did not differ at either age. FDS muscles from MI-IUGR lambs were smaller (P < 0.05) and exhibited reduced (P < 0.05) glucose oxidation and Akt phosphorylation but similar glucose uptake compared to controls when incubated in basal or insulin-spiked media. Similarly, hindlimb glucose oxidation was reduced (P < 0.05) in MI-IUGR lambs under basal and hyperinsulinemic conditions, but hindlimb glucose utilization did not differ from controls. Circulating urea nitrogen and cholesterol were reduced (P < 0.05) and triglycerides, high density lipoprotein-cholesterol, and glucose-to-insulin ratios were increased (P < 0.05) in MI-IUGR lambs. Glucose and insulin concentrations did not differ between groups during basal or hyperglycemic conditions. Although circulating monocyte and granulocyte concentrations were greater (P < 0.05) in MI-IUGR lambs, plasma TNFα was reduced (P < 0.05). FDS muscle contained greater (P < 0.05) TNFR1 and IκBα protein content. These findings indicate that maternofetal inflammation in late pregnancy results in fetal programming that impairs growth capacity, muscle glucose oxidation, and lipid homeostasis in offspring. Inflammatory indicators measured in this study appear to reflect heightened cytokine sensitivity in muscle and compensatory systemic responses to it.

Influence of Obstructive Sleep Apnea on Systemic Inflammation in Pregnancy

“…In the same way, maternal TNF-α concentration was inversely associated with birth weight in normal weight women ( 60 ). Human and animal studies also found that higher maternal plasma TNF-α concentration was associated with smaller birth weights ( 22 , 61 – 63 ). However, there are conflicting results, as other studies did not find correlations with either birth weight or fetal growth restriction ( 64 , 65 ).…”

Going Up Inflame: Reviewing the Underexplored Role of Inflammatory Programming in Stress-Induced Intrauterine Growth Restricted Livestock

“…When IUGR fetal sheep were made hyperglycemic or hyperinsulinemic near term, whole-body glucose oxidation was decreased even though whole-body glucose utilization remained unchanged (Limesand et al, 2007;Brown et al, 2015). Subsequent sheep studies confirmed that the reduction in glucose oxidation rates were muscle-specific and persisted after birth (Cadaret et al, 2019b;Yates et al, 2019;Gibbs et al, 2021;Posont et al, 2021). Four-fold greater circulating lactate concentrations together with greater hepatic expression of gluconeogenic genes in IUGR fetal sheep (Brown et al, 2015) indicate that lactate produced in greater amounts by IUGR skeletal muscle supports hepatic glucose production.…”

“…Offspring born with low birthweight due to IUGR initially continue to exhibit slower postnatal growth. For example, lambs born IUGR due to maternal heat stress or maternofetal inflammation remained about 20% smaller at 30 days of age, with comparable reductions in average daily gain ( Cadaret et al, 2019b ; Yates et al, 2019 ; Posont et al, 2021 ). As IUGR-born offspring reach the juvenile stage, many begin to exhibit postnatal catch-up growth, whereby their bodyweights equalize with uncompromised herdmates.…”

“…This is facilitated when circulating insulin binds to receptors on the muscle fiber surface and initiates rapid mobilization of sequestered glucose transporter 4 (Glut4) to the cell membrane, where it facilitates glucose diffusion into the cell ( Kubota et al, 2011 ). In addition to its effects on glucose uptake, insulin stimulation increased skeletal muscle glucose oxidation rates 1.5- to 4-fold in fetal sheep ( Brown et al, 2015 ; Cadaret et al, 2019 ) and 2- to 8-fold in growing lambs ( Barnes et al, 2019 ; Cadaret et al, 2019b ; Swanson et al, 2020 ; Posont et al, 2021 ). However, several studies have indicated that insulin/Akt signaling is impaired in IUGR muscle.…”

“…These nutrient-sparing fetal adaptations help to increase the chances for survival in utero but also create permanent metabolic changes that are detrimental to long-term health of the offspring ( Sharma et al, 2016a ; Kesavan and Devaskar, 2019 ; Posont and Yates, 2019 ). Identifying the exact mechanistic facilitators of these changes has been challenging, but one likely potential mechanism that has recently come to light is inflammatory programming ( Posont et al, 2018 , 2021 ; Cadaret et al, 2019 ). This review highlights findings that provide insight for how fetal stress leads to programmed changes in inflammatory pathways that regulate growth and metabolism, with a primary focus on the implications for meat animals.…”