Sustained maternal inflammation during the early third-trimester yields intrauterine growth restriction, impaired skeletal muscle glucose metabolism, and diminished β-cell function in fetal sheep1,2.

Maternal inflammation causes fetal intrauterine growth restriction (IUGR), but its impact on fetal metabolism is not known. Thus, our objective was to determine the impact of sustained maternal inflammation in late gestation on fetal inflammation, skeletal muscle glucose metabolism, and insulin secretion. Pregnant ewes were injected every third day from the 100th to 112th day of gestation (term = 150 d) with saline (controls) or lipopolysaccharide (LPS) to induce maternal inflammation and IUGR (MI-IUGR). Fetal femoral blood vessels were catheterized on day 118 to assess β-cell function on day 123, hindlimb glucose metabolic rates on day 124, and daily blood parameters from days 120 to 125. Fetal muscle was isolated on day 125 to assess ex vivo glucose metabolism. Injection of LPS increased (P < 0.05) rectal temperatures, circulating white blood cells, and plasma tumor necrosis factor α (TNFα) concentrations in MI-IUGR ewes. Maternal leukocytes remained elevated (P < 0.05) and TNFα tended to remain elevated (P < 0.10) compared with controls almost 2 wk after the final LPS injection. Total white blood cells, monocytes, granulocytes, and TNFα were also greater (P < 0.05) in MI-IUGR fetuses than controls over this period. MI-IUGR fetuses had reduced (P < 0.05) blood O2 partial pressures and greater (P < 0.05) maternofetal O2 gradients, but blood glucose and maternofetal glucose gradients did not differ from controls. Basal and glucose-stimulated insulin secretion were reduced (P < 0.05) by 32% and 42%, respectively, in MI-IUGR fetuses. In vivo hindlimb glucose oxidation did not differ between groups under resting conditions but was 47% less (P < 0.05) in MI-IUGR fetuses than controls during hyperinsulinemia. Hindlimb glucose utilization did not differ between fetal groups. At day 125, MI-IUGR fetuses were 22% lighter (P < 0.05) than controls and tended to have greater (P < 0.10) brain/BW ratios. Ex vivo skeletal muscle glucose oxidation did not differ between groups in basal media but was less (P < 0.05) for MI-IUGR fetuses in insulin-spiked media. Glucose uptake rates and phosphorylated-to-total Akt ratios were less (P < 0.05) in muscle from MI-IUGR fetuses than controls regardless of media. We conclude that maternal inflammation leads to fetal inflammation, reduced β-cell function, and impaired skeletal muscle glucose metabolism that persists after maternal inflammation ceases. Moreover, fetal inflammation may represent a target for improving metabolic dysfunction in IUGR fetuses.