The Metabolomic Signature of the Placenta in Spontaneous Preterm Birth.

The placenta is metabolically active and supports the growth of the fetus. We hypothesize that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may result in spontaneous preterm birth (SPTB). To explore this hypothesis, we performed a nested cased control study of metabolomic signatures in placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (≥38 weeks gestation). To control for the effects of gestational age on placenta metabolism, we also studied a subset of metabolites in non-laboring preterm and term Rhesus monkeys. Comprehensive quantification of metabolites demonstrated a significant elevation in the levels of amino acids, prostaglandins, sphingolipids, lysolipids, and acylcarnitines in SPTB placenta compared to term placenta. Additional quantification of placental acylcarnitines by tandem mass spectrometry confirmed the significant elevation in SPTB human, with no significant differences between midgestation and term placenta in Rhesus macaque. Fatty acid oxidation as measured by the flux of 3H-palmitate in SPTB placenta was lower than term. Collectively, significant and biologically relevant alterations in the placenta metabolome were identified in SPTB placenta. Altered acylcarnitine levels and fatty acid oxidation suggest that disruption in normal substrate metabolism is associated with SPTB.

Oral nitrite restores age-dependent phenotypes in eNOS-null mice.

Alterations in the synthesis and bioavailability of NO are central to the pathogenesis of cardiovascular and metabolic disorders. Although endothelial NO synthase-derived (eNOS-derived) NO affects mitochondrial long-chain fatty acid ß-oxidation, the pathophysiological significance of this regulation remains unclear. Accordingly, we determined the contributions of eNOS/NO signaling in the adaptive metabolic responses to fasting and in age-induced metabolic dysfunction. Four-month-old eNOS-/- mice are glucose intolerant and exhibit serum dyslipidemia and decreased capacity to oxidize fatty acids. However, during fasting, eNOS-/- mice redirect acetyl-CoA to ketogenesis to elevate circulating levels of ß-hydroxybutyrate similar to wild-type mice. Treatment of 4-month-old eNOS-/- mice with nitrite for 10 days corrected the hypertension and serum hyperlipidemia and normalized the rate of fatty acid oxidation. Fourteen-month-old eNOS-/- mice exhibited metabolic derangements, resulting in reduced utilization of fat to generate energy, lower resting metabolic activity, and diminished physical activity. Seven-month administration of nitrite to eNOS-/- mice reversed the age-dependent metabolic derangements and restored physical activity. While the eNOS/NO signaling is not essential for the metabolic adaptation to fasting, it is critical for regulating systemic metabolic homeostasis in aging. The development of age-dependent metabolic disorder is prevented by low-dose replenishment of bioactive NO.