Obesity Disrupts Rhythmic Clock Gene Expression in Maternal Adipose Tissue during Rat Pregnancy.

Obesity during pregnancy causes numerous maternal and fetal health complications, but the underlying mechanisms remain unclear. Adipose tissue dysfunction in obesity has previously been linked to disruption of the intrinsic adipose clock gene network that is crucial for normal metabolic function. This adipose clock also undergoes major change as part of the maternal metabolic adaptation to pregnancy, but whether this is affected by maternal obesity is unknown.

Diet-induced obesity reduces core body temperature across the estrous cycle and pregnancy in the rat.

Obesity during pregnancy causes adverse maternal and fetal health outcomes and programs offspring for adult-onset diseases, including cardiovascular disease. Obesity also disrupts core body temperature (T) regulation in nonpregnant rodents; however, it is unknown whether obesity alters normal maternal T adaptations to pregnancy. Since T is influenced by the circadian system, and both obesity and pregnancy alter circadian biology, it was hypothesized that obesity disrupts the normal rhythmic patterns of T before and during gestation.

Obesity-induced changes in hepatic and placental clock gene networks in rat pregnancy.

Maternal obesity induces pregnancy complications and disturbs fetal development, but the specific mechanisms underlying these outcomes are unclear. Circadian rhythms are implicated in metabolic complications associated with obesity, and maternal metabolic adaptations to pregnancy. Accordingly, obesity-induced circadian dysfunction may drive adverse outcomes in obese pregnancy.

Rhythmic Three-Part Harmony: The Complex Interaction of Maternal, Placental and Fetal Circadian Systems.

From the perspective of circadian biology, mammalian pregnancy presents an unusual biological scenario in which an entire circadian system (i.e., that of the fetus) is embodied within another (i.

Maternal-placental-fetal biodistribution of multimodal polymeric nanoparticles in a pregnant rat model in mid and late gestation.

Multimodal polymeric nanoparticles have many exciting diagnostic and therapeutic applications, yet their uptake and passage by the placenta, and applications in the treatment of pregnancy complications have not been thoroughly investigated. In this work, the maternal-fetal-placental biodistribution of anionic and cationic multimodal poly(glycidyl methacrylate) (PGMA) nanoparticles in pregnant rats at mid (ED10) and late (ED20) gestation was examined. Fluorescently-labelled and superparamagnetic PGMA nanoparticles functionalized with/without poly(ethyleneimine) (PEI) were administered to pregnant rats at a clinically-relevant dose and biodistribution and tissue uptake assessed.

Ontogeny of clock and KiSS-1 metastasis-suppressor (Kiss1) gene expression in the prepubertal mouse hypothalamus.

Kisspeptin is crucial for the generation of the circadian-gated preovulatory gonadotrophin-releasing hormone (GnRH)-LH surge in female rodents, with expression in the anteroventral periventricular nucleus (AVPV) peaking in the late afternoon of pro-oestrus. Given kisspeptin expression is established before puberty, the aim of the present study was to investigate kisspeptin and clock gene rhythms during the neonatal period. Anterior and posterior hypothalami were collected from C57BL/6J mice on Postnatal Days (P) 5, 15 and 25, at six time points across 24h, for analysis of gene expression by reverse transcription-quantitative polymerase chain reaction.

Obesity Disrupts the Rhythmic Profiles of Maternal and Fetal Progesterone in Rat Pregnancy.

Maternal obesity increases the risk of abnormal fetal growth, but the underlying mechanisms remain unclear. Because steroid hormones regulate fetal growth, and both pregnancy and obesity markedly alter circadian biology, we hypothesized that maternal obesity disrupts the normal rhythmic profiles of steroid hormones in rat pregnancy. Obesity was established by cafeteria (CAF) feeding for 8 wk prior to mating and throughout pregnancy.

Pregnancy Suppresses the Daily Rhythmicity of Core Body Temperature and Adipose Metabolic Gene Expression in the Mouse.

Maternal adaptations in lipid metabolism are crucial for pregnancy success due to the role of white adipose tissue as an energy store and the dynamic nature of energy needs across gestation. Because lipid metabolism is regulated by the rhythmic expression of clock genes, it was hypothesized that maternal metabolic adaptations involve changes in both adipose clock gene expression and the rhythmic expression of downstream metabolic genes. Maternal core body temperature (Tc) was investigated as a possible mechanism driving pregnancy-induced changes in clock gene expression.

Pregnancy-induced changes in the circadian expression of hepatic clock genes: implications for maternal glucose homeostasis.

Adaptations in maternal carbohydrate metabolism are particularly important in pregnancy because glucose is the principal energy substrate used by the fetus. As metabolic homeostasis is intricately linked to the circadian system via the rhythmic expression of clock genes, it is likely that metabolic adaptations during pregnancy also involve shifts in maternal circadian function. We hypothesized that maternal adaptation in pregnancy involves changes in the hepatic expression of clock genes, which drive downstream shifts in circadian expression of glucoregulatory genes.

Diurnal regulation of hypothalamic kisspeptin is disrupted during mouse pregnancy.

Kisspeptin, the neuropeptide product of the Kiss1 gene, is critical in driving the hypothalamic-pituitary-gonadal (HPG) axis. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (Arc) of the hypothalamus mediate differential effects, with the Arc regulating negative feedback of sex steroids and the AVPV regulating positive feedback, vital for the preovulatory surge and gated under circadian control. We aimed to characterize hypothalamic Kiss1 and Kiss1r mRNA expression in nonpregnant and pregnant mice, and investigate potential circadian regulation.

Maternal obesity induced by a 'cafeteria' diet in the rat does not increase inflammation in maternal, placental or fetal tissues in late gestation.

Introduction: Obesity during pregnancy can cause serious complications for maternal and infant health. While this has often been attributed to increased inflammation during obese pregnancy, human and animal studies exhibit variable results with respect to the inflammatory status of the mother, placenta and fetus. Cafeteria (CAF) feeding induces more inflammation than standard high-fat feeding in non-pregnant animal models.

Pregnancy-induced adaptations of the central circadian clock and maternal glucocorticoids.

Maternal physiological adaptations, such as changes to the hypothalamic-pituitary-adrenal (HPA) axis, are central to pregnancy success. Circadian variation of the HPA axis is dependent on clock gene rhythms in the hypothalamus, but it is not known whether pregnancy-induced changes in maternal glucocorticoid levels are mediated via this central clock. We hypothesized that hypothalamic expression of clock genes changes across mouse pregnancy and this is linked to altered HPA activity.

Rescue of glucocorticoid-programmed adipocyte inflammation by omega-3 fatty acid supplementation in the rat.

Background: Adverse fetal environments predispose offspring to pathologies associated with the metabolic syndrome. Previously we demonstrated that adult offspring of dexamethasone-treated mothers had elevated plasma insulin and pro-inflammatory cytokines, effects prevented by a postnatal diet enriched with omega (n)-3 fatty acids. Here we tested whether prenatal glucocorticoid excess also programmed the adipose tissue phenotype, and whether this outcome is rescued by dietary n-3 fatty acids.

Maternal dietary omega-3 fatty acids and placental function.

The developing fetus requires substantial amounts of fatty acids to support rapid cellular growth and activity. Although the fatty acid composition delivered to the fetus is largely determined by maternal circulating levels, the placenta preferentially transfers physiologically important long-chain polyunsaturated fatty acids (LC-PUFAs), particularly omega-3 (n-3) PUFAs. Maternal dietary supplementation with n-3 PUFAs during pregnancy has been shown to increase gestation length, enhance fetal growth, and reduce the risk of pregnancy complications, although the precise mechanisms governing these effects remain uncertain.

Maternal omega-3 fatty acid intake increases placental labyrinthine antioxidant capacity but does not protect against fetal growth restriction induced by placental ischaemia-reperfusion injury.

Placental oxidative stress plays a key role in the pathophysiology of several placenta-related disorders. Oxidative stress occurs when excess reactive oxygen species (ROS) damages cellular components, an outcome limited by antioxidant enzymes; mitochondrial uncoupling protein 2 (UCP2) also limits ROS production. We recently reported that maternal dietary omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation reduced placental oxidative damage and enhanced fetal and placental growth in the rats.

Postnatal dietary omega-3 fatty acid supplementation rescues glucocorticoid-programmed adiposity, hypertension, and hyperlipidemia in male rat offspring raised on a high-fat diet.

Fetal glucocorticoid excess programs several adverse outcomes in adult offspring, many of which can be prevented by postnatal, dietary omega-3 (n-3) fatty acids. Here we tested 2 separate hypotheses: 1) a postnatal high-fat diet exacerbates the glucocorticoid-programmed phenotype; and 2) postnatal, dietary n-3 fatty acids rescue programmed outcomes, even in the presence of a high-fat diet challenge. Pregnant Wistar rat dams were either untreated or administered dexamethasone acetate (Dex; 0.

Maternal dietary omega-3 fatty acid intake increases resolvin and protectin levels in the rat placenta.

Placental inflammation is associated with several pregnancy disorders. Inflammation is limited by anti-inflammatory and proresolving mechanisms, the latter partly mediated by resolvins and protectins derived from omega-3 polyunsaturated fatty acids (n-3PUFA). We examined effects of dietary n-3PUFAs on levels of resolvins, protectins, and lipoxygenase (ALOX) enzymes in the rat placenta.

Maternal dietary omega-3 fatty acid supplementation reduces placental oxidative stress and increases fetal and placental growth in the rat.

Placental oxidative stress plays a key role in the pathophysiology of several placenta-related disorders including intrauterine growth restriction. Oxidative stress occurs when accumulation of reactive oxygen species damages DNA, proteins, and lipids, an outcome normally limited by antioxidant defenses. Dietary supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFAs) may limit oxidative stress by increasing antioxidant capacity, but n-3 PUFAs are also highly susceptible to lipid peroxidation; so n-3 PUFA supplementation is potentially harmful.

Immunolocalisation of 11β-HSD-1 and -2, glucocorticoid receptor, mineralocorticoid receptor and Na+ K+-ATPase during the postnatal development of the rat epididymis.

Glucocorticoids have been implicated in male reproductive function and 11β-HSD-1 and -2, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), all of which are known to modulate glucocorticoid action, have been localised in the adult rat epididymis, but their developmental expression has not been investigated. Na(+)K(+)-ATPase activity, responsible for sodium transport, is induced by both mineralocorticoids and glucocorticoids in the kidney and colon, and has been localised in epididymal epithelium. This study examined the immunolocalisation of 11β-HSD-1 and -2, GR, MR and Na(+)K(+)-ATPase in rat epididymal epithelium (n = 5) at postnatal days (pnd) 1, 7, 15, 28, 40, 60, 75 and 104, and relative mRNA expression of 11β-HSD-1 and -2, and GR at pre-puberty (pnd 28) and post-puberty (pnd 75).

Oxysterols exert proinflammatory effects in placental trophoblasts via TLR4-dependent, cholesterol-sensitive activation of NF-κB.

Oxidized cholesterol metabolites (oxysterols) promote inflammation in a variety of cell types and are thought to be involved in a number of disease pathologies. Oxysterol concentrations are increased in pregnancy, together with systemic oxidative stress and inflammation. We tested the hypothesis that oxysterols 25-hydroxycholesterol (25-OHC) and 7-ketocholesterol (7-ketoC) promote placental trophoblast inflammation, and determined the mechanisms involved.

Circadian variation in placental and hepatic clock genes in rat pregnancy.

Clock genes drive circadian rhythms in a range of physiological processes both centrally and in peripheral tissues such as the liver. The aims of this study were to determine whether the two functionally-distinct zones of the rat placenta (junctional and labyrinth) differentially express clock genes and, if so, whether these exhibit circadian patterns. Rats were sampled from d 21 of pregnancy (term = d 23) and from diestrus I of the estrous cycle.

Placental ABCA1 and ABCG1 transporters efflux cholesterol and protect trophoblasts from oxysterol induced toxicity.

ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 mediate the efflux of cholesterol and other sterols. Both transporters are expressed on the fetal capillaries of the placenta and are involved in maternal-to-fetal cholesterol delivery. In this study, we report that ABCA1 and ABCG1 are also present on the syncytiotrophoblast, the maternal facing placental membrane.

Antioxidant defenses in the rat placenta in late gestation: increased labyrinthine expression of superoxide dismutases, glutathione peroxidase 3, and uncoupling protein 2.

Placental oxidative stress plays a key role in the pathophysiology of placenta-related disorders, most notably preeclampsia (PE) and intrauterine growth restriction (IUGR). Oxidative stress occurs when accumulation of reactive oxygen species (ROS) damages DNA, proteins and lipids, an outcome that is limited by antioxidant enzymes; mitochondrial uncoupling protein 2 (UCP2) may also limit oxidative stress by reducing ROS production. Here we characterized placental antioxidant defenses during normal gestation and following glucocorticoid-induced IUGR.

Developmental programming of adult adrenal structure and steroidogenesis: effects of fetal glucocorticoid excess and postnatal dietary omega-3 fatty acids.

Fetal glucocorticoid excess programs a range of detrimental outcomes in the adult phenotype, at least some of which may be due to altered adult adrenocortical function. In this study, we determined the effects of maternal dexamethasone treatment on offspring adrenal morphology and function, as well as the interactive effects of postnatal dietary omega-3 (n-3) fatty acids. This postnatal dietary intervention has been shown to alleviate many of the programming outcomes in this model, but whether this is via the effects on adrenal function is unknown.