Gestational disruptions in metabolic rhythmicity of the liver, muscle, and placenta affect fetal size

Abstract

Maternal metabolic adaptations are essential for successful pregnancy outcomes. We investigated how metabolic gestational processes are coordinated, whether there is a functional link with internal clocks, and whether disruptions are related to metabolic abnormalities in pregnancy, by studying day/night metabolic pathways in murine models and samples from pregnant women with normally grown and large-for-gestational age infants. In early mouse pregnancy, expression of hepatic lipogenic genes was up-regulated and uncoupled from the hepatic clock. In late mouse pregnancy, rhythmicity of energy metabolism-related genes in the muscle followed the patterns of internal clock genes in this tissue, and coincided with enhanced lipid transporter expression in the fetoplacental unit. Diurnal triglyceride patterns were disrupted in human placentas from pregnancies with large-for-gestational age infants and this overlapped with an increase in BMAL1 expression. Metabolic adaptations in early pregnancy are uncoupled from the circadian clock, whereas in late pregnancy, energy availability is mediated by coordinated muscle-placenta metabolic adjustments linked to internal clocks. Placental triglyceride oscillations in the third trimester of human pregnancy are lost in large-for-gestational age infants and may be regulated by BMAL1. In summary, disruptions in metabolic and circadian rhythmicity are associated with increased fetal size, with implications for the pathogenesis of macrosomia.—Papacleovoulou, G., Nikolova, V., Oduwole, O., Chambers, J., Vazquez-Lopez, M., Jansen, E., Nicolaides, K., Parker, M., Williamson, C. Gestational disruptions in metabolic rhythmicity of the liver, muscle, and placenta affect fetal size.

Circadian Clock, Time-Restricted Feeding and Reproduction

“…This study, which is consistent with other recent studies, showed that female Bmal1 −/− mice were infertile [98]. Bmal1 −/− mice had lower levels of fertilization, Bmal1 −/− mice obtained blastocyst numbers compared with that of WT mice after superovulation and being mated with WT males [98]. Additionally, Mereness et al reported that the deletion of Bmal1 had locus in ovarian granulosa cells (GCs) (Granulosa Cell Bmal1 KO; GCKO) or theca cells (TCs) (Theca Cell Bmal1 KO; TCKO) [99].…”

“…They found significantly lower levels of fertilization and obtained blastocyst numbers in Bmal1 −/− mice compared with that in Bmal1 +/+ mice, after superovulation and being mated with wild-type males [97]. This study, which is consistent with other recent studies, showed that female Bmal1 −/− mice were infertile [98]. Bmal1 −/− mice had lower levels of fertilization, Bmal1 −/− mice obtained blastocyst numbers compared with that of WT mice after superovulation and being mated with WT males [98].…”

“…Investigating the relationship between the internal circadian clock and metabolic abnormalities in pregnancies, serum triglycerides in mice increase in later pregnancy and fluctuate throughout the light/dark cycle. In humans, postprandial serum triglyceride levels are high [98]. These data suggest that there is an increase in serum triglyceride levels in the third trimester after a high-calorie lunch compared to levels in non-pregnant women.…”

Enhanced Microbial Bile Acid Deconjugation and Impaired Ileal Uptake in Pregnancy Repress Intestinal Regulation of Bile Acid Synthesis

“…Mice were sacrificed on day 0 or day 18 of pregnancy, resulting in n = 6‐8 per group. Separate cohorts of C57BL/6 mice were sacrificed at increasing gestational ages (days 2, 7, 10, 14, and 18; n = 6‐7 per time point), as described …”

Chronodisruption: effects on reproduction, transgenerational health of offspring and epigenome

“…Thus, even though the exact mechanisms are not known, the current data indicates the likely importance of maternal circadian signals such as melatonin, in driving rhythmic placental function (Chuffa et al 2019). In addition, the raised triglyceride levels observed in human placentas from pregnancies with large-for-gestational age infants are found to be associated with upregulated expression of the clock gene BMAL1 (Papacleovoulou et al 2017). Ohhashi and colleagues investigated 115 cases of placental abruption retrospectively and reported that abdominal pain and adverse perinatal outcomes including perinatal death showed significant circadian variation (Ohhashi et al 2017).…”