Early postnatal caloric restriction protects adult male intrauterine growth-restricted offspring from obesity.

Postnatal ad libitum caloric intake superimposed on intrauterine growth restriction (IUGR) is associated with adult-onset obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). We hypothesized that this paradigm of prenatal nutrient deprivation-induced programming can be reversed with the introduction of early postnatal calorie restriction. Ten-month-old male rats exposed to either prenatal nutrient restriction with ad libitum postnatal intake (IUGR), pre- and postnatal nutrient restriction (IPGR), or postnatal nutrient restriction limited to the suckling phase (50% from postnatal [PN]1 to PN21) (PNGR) were compared with age-matched controls (CON). Visceral adiposity, metabolic profile, and insulin sensitivity by hyperinsulinemic-euglycemic clamps were examined. The 10-month-old male IUGR group had a 1.5- to 2.0-fold increase in subcutaneous and visceral fat (P < 0.0002) while remaining euglycemic, insulin sensitive, inactive, and exhibiting metabolic inflexibility (Vo(2)) versus CON. The IPGR group remained lean, euglycemic, insulin sensitive, and active while maintaining metabolic flexibility. The PNGR group was insulin sensitive, similar to IPGR, but less active while maintaining metabolic flexibility. We conclude that IUGR resulted in obesity without insulin resistance and energy metabolic perturbations prior to development of glucose intolerance and T2DM. Postnatal nutrient restriction superimposed on IUGR was protective, restoring metabolic normalcy to a lean and active phenotype

The Placental Transcriptome in Late Gestational Hypoxia Resulting in Murine Intrauterine Growth Restriction Parallels Increased Risk of Adult Cardiometabolic Disease.

Intrauterine growth restriction (IUGR) enhances risk for adult onset cardiovascular disease (CVD). The mechanisms underlying IUGR are poorly understood, though inadequate blood flow and oxygen/nutrient provision are considered common endpoints. Based on evidence in humans linking IUGR to adult CVD, we hypothesized that in murine pregnancy, maternal late gestational hypoxia (LG-H) exposure resulting in IUGR would result in (1) placental transcriptome changes linked to risk for later CVD, and 2) adult phenotypes of CVD in the IUGR offspring. After subjecting pregnant mice to hypoxia (10.5% oxygen) from gestational day (GD) 14.5 to 18.5, we undertook RNA sequencing from GD19 placentas. Functional analysis suggested multiple changes in structural and functional genes important for placental health and function, with maximal dysregulation involving vascular and nutrient transport pathways. Concordantly, a ~10% decrease in birthweights and ~30% decrease in litter size was observed, supportive of placental insufficiency. We also found that the LG-H IUGR offspring exhibit increased risk for CVD at 4 months of age, manifesting as hypertension, increased abdominal fat, elevated leptin and total cholesterol concentrations. In summary, this animal model of IUGR links the placental transcriptional response to the stressor of gestational hypoxia to increased risk of developing cardiometabolic disease

Gestational food restriction decreases placental interleukin-10 expression and markers of autophagy and endoplasmic reticulum stress in murine intrauterine growth restriction

Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies and often results in short- and long-term sequelae for offspring. The mechanisms underlying IUGR are poorly understood, but it is known that healthy placentation is essential for nutrient provision to fuel fetal growth, and is regulated by immunologic inputs. We hypothesized that in pregnancy, maternal food restriction (FR) resulting in IUGR would decrease the overall immunotolerant milieu in the placenta, leading to increased cellular stress and death. Our specific objectives were to evaluate (1) key cytokines (eg, IL-10) that regulate maternal-fetal tolerance, (2) cellular processes (autophagy and endoplasmic reticulum [ER] stress) that are immunologically mediated and important for cellular survival and functioning, and (3) the resulting IUGR phenotype and placental histopathology in this animal model. After subjecting pregnant mice to mild and moderate FR from gestational day 10 to 19, we collected placentas and embryos at gestational day 19. We examined RNA sequencing data to identify immunologic pathways affected in IUGR-associated placentas and validated messenger RNA expression changes of genes important in cellular integrity. We also evaluated histopathologic changes in vascular and trophoblastic structures as well as protein expression changes in autophagy, ER stress, and apoptosis in the mouse placentas. Several differentially expressed genes were identified in FR compared with control mice, including a considerable subset that regulates immune tolerance, inflammation, and cellular integrity. In summary, maternal FR decreases the anti-inflammatory effect of IL-10 and suppresses placental autophagic and ER stress responses, despite evidence of dysregulated vascular and trophoblast structures leading to IUGR

Differential methylation of the micro‐RNA 7b gene targets postnatal maturation of murine neuronal Mecp2 gene expression

DNA methylation and microRNAs (miRNAs) play crucial roles in maturation of postnatal mouse neurons. Aberrant DNA methylation and/or altered miRNA expression cause postnatal neurodevelopmental disorders. In general, DNA methylation in the 5'-flanking region suppresses gene expression through recruitment of methyl-CpG binding domain proteins (MBPs) to the cytosine residues of CpG dinucleotides. X-linked MeCP2 (methyl-CpG binding protein 2), a member of MBPs, is a methylation-associated transcriptional repressor with other functions in the central nervous system (CNS). miRNAs negatively regulate gene expression by targeting the 3'-untranslated region (3'UTR). Some miRNA genes harboring or being embedded in CpG islands undergo methylation-mediated silencing. One such miRNA is miR-7b which is differentially expressed through stages of neurodevelopment. In our present study, we focused on a canonical CpG island located in the 5'-flanking region of the murine miR-7b gene. Hypermethylation of this CpG island down-regulates miR-7b while recruiting MeCP2 to the methylated CpG dinucleotides. Meanwhile, Mecp2, a target of miR-7b, was up-regulated due to lack of restrain exerted by miR-7b during maturation of postnatal (PN) mouse neurons between PN3 and PN14. Our results indicate that miR-7b is a direct downstream gene transcriptional target while also being a negative post-transcriptional regulator of Mecp2 expression. We speculate that this bidirectional feed-back autoregulatory function of miR-7b and Mecp2 while linking DNA methylation and miRNA action maintains the homeostatic control of gene expression necessary during postnatal maturation of mammalian neurons

Early postnatal caloric restriction protects adult male intrauterine growth-restricted offspring from obesity.

Postnatal ad libitum caloric intake superimposed on intrauterine growth restriction (IUGR) is associated with adult-onset obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). We hypothesized that this paradigm of prenatal nutrient deprivation-induced programming can be reversed with the introduction of early postnatal calorie restriction. Ten-month-old male rats exposed to either prenatal nutrient restriction with ad libitum postnatal intake (IUGR), pre- and postnatal nutrient restriction (IPGR), or postnatal nutrient restriction limited to the suckling phase (50% from postnatal [PN]1 to PN21) (PNGR) were compared with age-matched controls (CON). Visceral adiposity, metabolic profile, and insulin sensitivity by hyperinsulinemic-euglycemic clamps were examined. The 10-month-old male IUGR group had a 1.5- to 2.0-fold increase in subcutaneous and visceral fat (P < 0.0002) while remaining euglycemic, insulin sensitive, inactive, and exhibiting metabolic inflexibility (Vo(2)) versus CON. The IPGR group remained lean, euglycemic, insulin sensitive, and active while maintaining metabolic flexibility. The PNGR group was insulin sensitive, similar to IPGR, but less active while maintaining metabolic flexibility. We conclude that IUGR resulted in obesity without insulin resistance and energy metabolic perturbations prior to development of glucose intolerance and T2DM. Postnatal nutrient restriction superimposed on IUGR was protective, restoring metabolic normalcy to a lean and active phenotype

MicroRNA 122 Reflects Liver Injury in Children with Intestinal Failure–Associated Liver Disease Treated with Intravenous Fish Oil

BackgroundThere is evidence that microRNA (MIR) 122 is a biomarker for various liver diseases in adults and children. To date, MIR122 has not been explored in children with intestinal failure-associated liver disease (IFALD, or hyperbilirubinemia associated with prolonged parenteral nutrition).ObjectivesThis study's purpose was to investigate changes in plasma miR-122, correlate miR-122 with serum liver function tests and enzymes, and investigate changes in whole blood transcripts including miR-122 targets in a group of children with IFALD who received pure intravenous fish oil (FO) as a treatment for cholestasis.MethodsThis was a prospective, observational study that enrolled children with IFALD who received intravenous FO (1 g/kg/d) and whose cholestasis resolved with FO. Plasma miR-122 was measured using reverse transcription-quantitative real-time PCR, and whole blood miR-122 targets were quantified using RNA sequencing.ResultsFourteen subjects with median age 6 mo (IQR: 3-65 mo) were enrolled. RNA sequence data were available for 4 subjects. When compared with the start of FO, median miR-122 concentrations at 6 mo of FO therapy decreased [1.0 (IQR: 1.0-1.0) compared with 0.04 (IQR: 0.01-0.6), P = 0.009]. At the start of FO, miR-122 correlated with conjugated bilirubin (r = 0.56; P = 0.038). At ∼3 mo of FO, miR-122 correlated with conjugated bilirubin (r = 0.56; P = 0.045). Reactive oxygen species, heme metabolism, coagulation, adipogenesis, IL-6-Janus kinase-signal transducer and activator of transcription (JAK-STAT) 3, IL-2-STAT5, transforming growth factor-β, TNF-α, inflammatory response, mammalian target of rapamycin gene families (normalized enrichment scores < -1.4), and miR-122 target genes were significantly downregulated with FO.ConclusionsIn this small cohort of young children with IFALD, miR-122 decreased with FO therapy and correlated with conjugated bilirubin. Key pathways involving oxidation, inflammation, cellular differentiation, and nutrient regulation were downregulated. Data from this study provide information about IFALD and FO. This trial was registered at www.clinicaltrials.gov as NCT00969332

Gestational food restriction decreases placental interleukin-10 expression and markers of autophagy and endoplasmic reticulum stress in murine intrauterine growth restriction.

Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies and often results in short- and long-term sequelae for offspring. The mechanisms underlying IUGR are poorly understood, but it is known that healthy placentation is essential for nutrient provision to fuel fetal growth, and is regulated by immunologic inputs. We hypothesized that in pregnancy, maternal food restriction (FR) resulting in IUGR would decrease the overall immunotolerant milieu in the placenta, leading to increased cellular stress and death. Our specific objectives were to evaluate (1) key cytokines (eg, IL-10) that regulate maternal-fetal tolerance, (2) cellular processes (autophagy and endoplasmic reticulum [ER] stress) that are immunologically mediated and important for cellular survival and functioning, and (3) the resulting IUGR phenotype and placental histopathology in this animal model. After subjecting pregnant mice to mild and moderate FR from gestational day 10 to 19, we collected placentas and embryos at gestational day 19. We examined RNA sequencing data to identify immunologic pathways affected in IUGR-associated placentas and validated messenger RNA expression changes of genes important in cellular integrity. We also evaluated histopathologic changes in vascular and trophoblastic structures as well as protein expression changes in autophagy, ER stress, and apoptosis in the mouse placentas. Several differentially expressed genes were identified in FR compared with control mice, including a considerable subset that regulates immune tolerance, inflammation, and cellular integrity. In summary, maternal FR decreases the anti-inflammatory effect of IL-10 and suppresses placental autophagic and ER stress responses, despite evidence of dysregulated vascular and trophoblast structures leading to IUGR