Postnatal Body Growth Research Articles

Biomarkers of growth and carbohydrate metabolism in neonatal rats supplemented with fish oil and/or antioxidants during intermittent hypoxia

ObjectiveExtremely low gestational age neonates (ELGANs) experience frequent intermittent hypoxia (IH) episodes during therapeutic oxygen. ELGANs exhibit poor postnatal growth requiring lipid supplementation. Lipids are targets of reactive oxygen species resulting in lipid peroxidation and cell death, particularly in preterm infants with compromised antioxidant systems. We tested the hypothesis that early supplementation with lipids and/or antioxidants promotes growth and influences biomarkers of carbohydrate metabolism in neonatal rats exposed to IH. DesignNewborn rats (n = 18/group) were exposed to brief hypoxia (12% O2) during hyperoxia (50% O2), or room air (RA), from birth (P0) to P14 during which they received daily oral supplementation with: 1) fish oil; 2) Coenzyme Q10 (CoQ10) in olive oil; 3) glutathione nanoparticles (nGSH); 4) fish oil+CoQ10; or 5) olive oil. At P21, plasma samples were assessed for glucose, insulin, glucokinase (GCK), glucagon, glucagon-like peptide (GLP)-1, growth hormone (GH), corticosterone, and ghrelin. Liver was assessed for histopathology, apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL stain), and GH, insulin-like growth factor (IGF)-I, GH binding protein (GHBP), and IGF binding protein (IGFBP)-3. ResultsNeonatal IH resulted in decreased liver weight and liver/body weight ratios, as well as hepatocyte swelling, steatosis, and apoptosis, which were attenuated with fish oil, nGSH, and combined fish oil+CoQ10. IH also decreased plasma glucose, insulin, GCK, and ghrelin, but increased GLP-1. All treatments improved plasma glucose in IH, but insulin was higher with CoQ10 and nGSH only. Glucagon was increased with CoQ10, fish oil, and CoQ10 + fish oil, while corticosterone was higher with nGSH and CoQ10 + fish oil. IGF-I and IGFBP-3 were significantly higher in the liver with CoQ10 in IH, while deficits in GH were noted with CoQ10 and fish oil in RA and IH. Treatment with nGSH and combined CoQ10 + fish oil reduced IGF-I in RA and IH but increased IGFBP-3. ConclusionsNeonatal IH impairs liver growth with significant hepatocyte damage. Of all supplements in IH, nGSH and combined fish oil+CoQ10 were most effective for preserving liver growth and carbohydrate metabolism. Data suggest that these supplements may improve poor postnatal organ and body growth; and metabolic dysfunction associated with neonatal IH.

Programming of postnatal phenotype caused by exposure of cultured embryos from Brahman cattle to colony-stimulating factor 2 and serum.

Alterations in the environment of the preimplantation embryo can affect competence to establish pregnancy and phenotype of resultant calves. In this study, the bovine embryo produced in vitro was used to evaluate postnatal programming actions of the embryokine colony-stimulating factor 2 (CSF2) and serum, which is a common additive of culture media. Oocytes were collected by ovum pick up from Brahman donors and fertilized with semen from Brahman bulls. Embryos were randomly assigned to one of the three treatments: vehicle, CSF2 10 ng/mL, or 1% (v/v) serum. Treatments were added to the culture medium from day 5 to 7 after fertilization. Blastocysts were harvested on day 7 and transferred into crossbred recipients. Postnatal body growth and Longissimus dorsi muscle characteristics of the resultant calves were measured. The percent of cleaved embryos becoming blastocysts was increased by serum and, to a lesser extent, CSF2. Treatment did not affect survival after embryo transfer but gestation length was shortest for pregnancies established with serum-treated embryos. Treatment did not significantly affect postnatal body weight or growth. At 3 mo of age, CSF2 calves had lower fat content in the Longissimus dorsi muscle and less subcutaneous fat over the muscle than vehicle calves. There was a tendency for cross-sectional area of the muscle to be smaller for serum calves than vehicle calves. Results confirm the importance of the preimplantation period as a window to modulate postnatal phenotype of resultant calves. In particular, CSF2 exerted actions during the preimplantation period to program characteristics of accumulation of intramuscular and subcutaneous fat of resultant calves. The use of a low serum concentration in culture medium from day 5 to 7 of development can increase the yield of transferrable embryos without causing serious negative consequences for the offspring.

In a Preclinical Model of Prenatal Alcohol Exposure, an Iron Supplementation Intervention Reduces Anxiety-Like Behavior in Both Sexes and Improves Growth in Males

Abstract Objectives Both prenatal iron deficiency and prenatal alcohol exposure (PAE) decrease body weight, increase susceptibility to anxiety, and impair memory and learning in the offspring. PAE itself causes fetal iron deficiency, even when mothers consume sufficient iron. We hypothesized that iron supplementation in PAE pregnancies would not alter offspring growth but would improve measures of anxiety, learning, and memory. Methods Pregnant Long-Evans rats received 5 g/kg/day ethanol or isocaloric maltodextrin (split-dose) from gestational day (GD) 13.5–19.5 and received 6 mg/kg/day iron as ferric sulfate or water from GD12.5–19.5. Male and female offspring were weighed regularly after birth and underwent elevated plus maze (postnatal day (P) 27), open field (P28), novel object recognition (P29–30), T-maze (P32–40), and fear conditioning (P42–50) tests. Mixed model analysis was used to determine significance of the effects of PAE, iron, and sex. Results PAE reduced postnatal body growth in both male (P = 0.028) and female (P = 0.026) offspring. In both sexes, PAE interacted with age to affect growth (P < 0.001) from P5 to P50. In males but not females, iron supplementation interacted with age (P = 0.044) and age and PAE (P = 0.045) to improve growth in PAE + iron males, such that their weights approached control weights by P50. On the elevated plus maze, iron supplementation, regardless of PAE or sex, increased time spent on the open arms by 39–118%, indicating reduced anxiety-like behavior (P = 0.030). On the open field test, time spent in the center was not affected by PAE, iron, or sex (P’s > 0.200). On the novel object recognition test, at delays of both 1 and 24 hours, all groups (except MD + Iron Males with 24-hour delay) recognized the novel object better than chance (P’s < 0.040), but recognition at both time delays was not affected by PAE, iron, or sex (P’s > 0.120), showing that these did not affect recognition memory. On the T-maze and fear conditioning tests, which assess learning and memory, PAE, iron, and sex had no effect on the results (P’s > 0.080). Conclusions This work is the first to investigate gestational iron supplementation as an intervention for alcohol-exposed pregnancies. These results suggest iron supplementation may improve outcomes such as growth in males and anxiety in both sexes in alcohol-exposed populations. Funding Sources NIAAA NIDDK.

"Females Are Not Just 'Protected' Males": Sex-Specific Vulnerabilities in Placenta and Brain after Prenatal Immune Disruption.

Current perceptions of genetic and environmental vulnerabilities in the developing fetus are biased toward male outcomes. An argument is made that males are more vulnerable to gestational complications and neurodevelopmental disorders, the implication being that an understanding of disrupted development in males is sufficient to understand causal mechanisms that are assumed to be similar but attenuated in females. Here we examine this assumption in the context of immune-driven alterations in fetal brain development and related outcomes in female and male mice. Pregnant C57BL/6 mice were treated with low-dose lipopolysaccharide at embryonic day 12.5. Placental pathology, acute fetal brain inflammation and hypoxia, long-term changes in adult cortex cytoarchitecture, altered densities and ratio of excitatory (Satb2+) to inhibitory (parvalbumin+) neuronal subtypes, postnatal growth, and behavior outcomes were compared between male and female offspring. We find that while males experience more pronounced placental pathology, fetal brain hypoxia, depleted PV and Satb2+ densities, and social and learning-related behavioral abnormalities, females exhibit unique acute inflammatory signaling in fetal brain, postnatal growth delay, opposite alterations in cortical PV densities, changes in juvenile behavior, delayed postnatal body growth, and elevated anxiety-related behavior as adults. While males are more severely impacted by prenatal immune disruption by several measures, females exposed to the same insult exhibit a unique set of vulnerabilities and developmental consequences that is not present in males. Our results clearly outline disparate sex-specific features of prenatal vulnerability to inflammatory insults and warn against the casual extrapolation of male disease mechanisms to females.

Myelinating Schwann Cell Polarity and Mechanically-Driven Myelin Sheath Elongation.

Myelin sheath geometry, encompassing myelin sheath thickness relative to internodal length, is critical to optimize nerve conduction velocity and these parameters are carefully adjusted by the myelinating cells in mammals. In the central nervous system these adjustments could regulate neuronal activities while in the peripheral nervous system they lead to the optimization and the reliability of the nerve conduction velocity. However, the physiological and cellular mechanisms that underlie myelin sheath geometry regulation are not yet fully elucidated. In peripheral nerves the myelinating Schwann cell uses several molecular mechanisms to reach and maintain the correct myelin sheath geometry, such that myelin sheath thickness and internodal length are regulated independently. One of these mechanisms is the epithelial-like cell polarization process that occurs during the early phases of the myelin biogenesis. Epithelial cell polarization factors are known to control cell size and morphology in invertebrates and mammals making these processes critical in the organogenesis. Correlative data indicate that internodal length is regulated by postnatal body growth that elongates peripheral nerves in mammals. In addition, the mechanical stretching of peripheral nerves in adult animals shows that myelin sheath length can be increased by mechanical cues. Recent results describe the important role of YAP/TAZ co-transcription factors during Schwann cell myelination and their functions have linked to the mechanotransduction through the HIPPO pathway and the epithelial polarity factor Crb3. In this review the molecular mechanisms that govern mechanically-driven myelin sheath elongation and how a Schwann cell can modulate internodal myelin sheath length, independent of internodal thickness, will be discussed regarding these recent data. In addition, the potential relevance of these mechanosensitive mechanisms in peripheral pathologies will be highlighted.

Molecular interactions of EphA4, growth hormone receptor, Janus kinase 2, and signal transducer and activator of transcription 5B.

We previously reported that EphA4, a member of the Eph family of receptor tyrosine kinases, is an important modulator of growth hormone (GH) signaling, leading to augmented synthesis of insulin-like growth factor 1 (IGF1) for postnatal body growth. In the present study, we report the molecular interactions of EphA4, GH receptor (GHR), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 5B (STAT5B). EphA4 binds to GHR at both its extracellular and intracellular domains and phosphorylates GHR when stimulated with a ligand. The cytoplasmic domain of EphA4 binds to the carboxy-terminus of JAK2 in contrast to the known binding of GHR to the amino-terminus. STAT5B binds to the amino-terminal kinase domain of EphA4. Ligand-activated EphA4 and JAK2 phosphorylate each other and STAT5B, but JAK2 does not appear to phosphorylate EphA4-bound STAT5B. Ligand-activated EphA4 induces the nuclear translocation of STAT5B in a JAK2-independent manner. GHR expression is required for the activation of STAT5B signaling, even via the JAK2-independent pathway. Various ephrins that have affinity for EphA4 induce STAT5B phosphorylation. These findings suggest the molecular mechanisms by which ephrin/EphA4 signaling enhances the canonical GH-IGF1 axis.

Role of TrkB during the postnatal development of the rat carotid body

Brain-derived neurotrophic factor (BDNF) supports innervation of the carotid body by neurons projecting from the petrosal ganglion. Although carotid body glomus cells also express TrkB, BDNF's high affinity receptor, the role of BDNF in carotid body growth and O2 sensitivity has not been studied. Neonatal rats were treated with the TrkB antagonist K252a (100μgkg−1, i.p., b.i.d.) or vehicle on postnatal days P0–P6 and studied on P7. Carotid body volume was decreased by 35% after chronic K252a (P<0.001); a reduction in carotid body size was also elicited using the more selective TrkB antagonist ANA-12 (500μgkg−1, i.p., b.i.d.). In contrast, single-unit chemoafferent responses to 5% O2, measured in vitro, were unaffected by chronic K252a administration. Normoxic and hypoxic ventilation, measured by head–body plethysmography, were also normal after chronic K252a administration, but acute K252a administration produced a slower, deeper breathing pattern during the transition into hypoxia. These data suggest that BDNF regulates postnatal carotid body growth but does not influence the development of glomus cell O2 sensitivity.

An intrauterine catch-up growth regimen increases food intake and post-natal growth in rats

Nutritional conditions during the intrauterine stage are an important developmental programming factor that can affect the growth and metabolic status during foetal development and permanently alter the phenotypes of newborn offspring and adults. This study was performed to examine the effects of intrauterine catch-up growth (IUCG) on food intake, post-natal body growth and the metabolic status of offspring and growing rats. Control pregnant rats were fed ad libitum during the entire gestation period. For the IUCG regimen, pregnant rats were fed 50% of the food of the controls from pregnancy days 4 through 11 (8 days), followed by ad libitum feeding from pregnancy days 12 through parturition. The birth weight of offspring was not affected by the IUCG regimen. At weaning, offspring from each treatment group were assigned to two groups and given either a normal diet or high-fat diet (HFD) for 12 weeks until 103 days of age. In the normal diet group, the IUCG offspring showed a 9.0% increase (P < 0.05) in total food intake, were 11.2% heavier (p < 0.05) at 103 days of age and had an 11.0% greater (p < 0.05) daily weight gain compared with control offspring. The IUCG regimen did not affect body glucose and lipid metabolism. After exposure to the HFD, the IUCG regimen has not exacerbated metabolic disorders. In conclusion, our findings suggest that the IUCG nutritional regimen during pregnancy can increase the food intake and post-natal body growth of offspring without inducing metabolic disorders such as obesity and insulin resistance. The IUCG nutritional regimen might be used to improve the food intake and post-natal body growth of domestic animals.

Body size regulation and insulin-like growth factor signaling.

How animals achieve their specific body size is a fundamental, but still largely unresolved, biological question. Over the past decades, studies on the insect model system have provided some important insights into the process of body size determination and highlighted the importance of insulin/insulin-like growth factor signaling. Fat body, the Drosophila counterpart of liver and adipose tissue, senses nutrient availability and controls larval growth rate by modulating peripheral insulin signaling. Similarly, insulin-like growth factor I produced from liver and muscle promotes postnatal body growth in mammals. Organismal growth is tightly coupled with the process of sexual maturation wherein the sex steroid hormone attenuates body growth. This review summarizes some important findings from Drosophila and mammalian studies that shed light on the general mechanism of animal size determination.

Crosstalk of Humoral and Cell-Cell Contact-Mediated Signals in Postnatal Body Growth

The growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis mediates postnatal body growth. The GH receptor has been regarded as the sole receptor that mediates the Janus kinase 2 (JAK2)/signal transducers and activators of the transcription 5B (STAT5B) signal toward IGF1 synthesis. Here, we report a signaling pathway that regulates postnatal body growth through EphA4, a member of the Eph family of receptor tyrosine kinases and a mediator of the cell-cell contact-mediated signaling. EphA4 forms a complex with the GH receptor, JAK2, and STAT5B and enhances Igf1 expression predominantly via the JAK2-dependent pathway, with some direct effect on STAT5B. Mice with a defective Epha4 gene have a gene dose-dependent short stature and low plasma IGF1 levels. Igf1 messenger RNA (mRNA) in the liver and many other tissues was also significantly reduced in Epha4-knockout mice, whereas pituitary Gh mRNA and plasma GH levels were not. These findings suggest that the local cell-cell contact-mediated ephrin/EphA4 signal is as important as the humoral GH signal in IGF1 synthesis and body size determination.

Carotid body growth and the critical period for hyperoxia‐induced developmental plasticity in rats

Chronic postnatal hyperoxia elicits both transient and long‐lasting plasticity in the control of breathing, primarily through effects at the carotid body. We hypothesized that the critical period for long‐lasting changes to the hypoxic ventilatory response (HVR) would correspond to the period of postnatal carotid body growth (i.e., morphological plasticity), while transient attenuation of carotid body O2 sensitivity would occur independent of postnatal age. Although the critical period for long‐lasting attenuation of the HVR is limited to the first two postnatal weeks (Bavis et al., J. Appl. Physiol. 92: 1013–1018, 2002), we observed a substantial increase in carotid body volume through 12 wk of age; growth rates and glomus cell division (BrdU labeling) appeared to slow by 8–10 wk of age. In rats exposed to 7 d of 60% O2 beginning at ~4 wk of age, normoxic ventilation was reduced but HVR was unchanged; normoxic ventilation recovered within 7 d of returning to room air. We conclude that (1) carotid body growth is not the only factor determining the critical period for long‐lasting changes to the HVR and (2) transient changes to the HVR are also limited to exposures during early postnatal development (i.e., prior to P28). Supported by NIH grant P20 RR‐016463 (Maine INBRE).

Early retinal blood vessel growth in normal and growth restricted rat pups raised in oxygen and room air

Background/aimsPremature infants are born with incompletely vascularised retinas and are at a risk of developing retinopathy of prematurity (ROP). Rate of prenatal and postnatal body growth is important in the...

Postnatal-Onset Microcephaly: Pathogenesis, Patterns of Growth, and Prediction of Outcome

Although children with postnatal-onset microcephaly (POM) generally have poor development, we speculated that better somatic growth would predict better development in these children. We followed 57 children with POM for an average of 4.2 years (13 encephaloclastic, 14 dysgenetic, 6 with Rett syndrome, 24 idiopathic) and calculated the developmental quotient (DQ) at each visit (DQ > 0.70 was considered normal). SD scores (SDS) for measurements were analyzed using a repeated measures mixed-effects model to assess effect of weight, height, head circumference (HC), and age on DQ. Pearson's correlation was used to examine the independent influence of each variable on final DQ. Forty-four children (77%) had a low DQ (mean: 0.33), but 13 (23%) had a normal DQ (mean: 0.93), including 10 idiopathic and 3 encephaloclastic. Mean HC fell below -2 SDS in all before 1 year (destructive at 3.3 months, idiopathic low-DQ at 7.5 months, dysgenetic at 8.5 months, Rett syndrome at 11 months, and idiopathic normal-DQ at 11.5 months). Mean weights and heights both fell below -2 SDS for all low-DQ groups but remained normal in both normal-DQ groups. Weight, height, and HC were independent predictors of DQ (P < .0001). Final DQ correlated with weight (r = 0.27), height (r = 0.41), and HC (r = 0.13). Most children with POM have poor later development. Whatever the cause of POM, persons in whom postnatal body growth (weight, height, HC) is better sustained have more favorable development, and in one-quarter of such persons (mostly idiopathic POM), final DQ is normal.

Intersubspecific subcongenic mouse strain analysis reveals closely linked QTLs with opposite effects on body weight

A previous genome-wide QTL study revealed many QTLs affecting postnatal body weight and growth in an intersubspecific backcross mouse population between the C57BL/6J (B6) strain and wild Mus musculus castaneus mice captured in the Philippines. Subsequently, several closely linked QTLs for body composition traits were revealed in an F(2) intercross population between B6 and B6.Cg-Pbwg1, a congenic strain on the B6 genetic background carrying the growth QTL Pbwg1 on proximal chromosome 2. However, no QTL affecting body weight has been duplicated in the F(2) population, except for mapping an overdominant QTL that causes heterosis of body weight. In this study, we developed 17 intersubspecific subcongenic strains with overlapping and nonoverlapping castaneus regions from the B6.Cg-Pbwg1 congenic strain in order to search for and genetically dissect QTLs affecting body weight into distinct closely linked loci. Phenotypic comparisons of several developed subcongenic strains with the B6 strain revealed that two closely linked but distinct QTLs that regulate body weight, named Pbwg1.11 and Pbwg1.12, are located on an 8.9-Mb region between D2Mit270 and D2Mit472 and on the next 3.6-Mb region between D2Mit205 and D2Mit182, respectively. Further analyses using F(2) segregating populations obtained from intercrosses between B6 and each of the two selected subcongenic strains confirmed the presence of these two body weight QTLs. Pbwg1.11 had an additive effect on body weight at 6, 10, and 13 weeks of age, and its castaneus allele decreased it. In contrast, the castaneus allele at Pbwg1.12 acted in a dominant fashion and surprisingly increased body weight at 6, 10, and 13 weeks of age despite the body weight of wild castaneus mice being 60% of that of B6 mice. These findings illustrate the complex genetic nature of body weight regulation and support the importance of subcongenic mouse analysis to dissect closely linked loci.

Principal pathogenetic components and biological endophenotypes in autism spectrum disorders

Autism is a complex neurodevelopmental disorder, likely encompassing multiple pathogenetic components. The aim of this study is to begin identifying at least some of these components and to assess their association with biological endophenotypes. To address this issue, we recruited 245 Italian patients with idiopathic autism spectrum disorders and their first-degree relatives. Using a stepwise approach, patient and family history variables were analyzed using principal component analysis ("exploratory phase"), followed by intra- and inter-component cross-correlation analyses ("follow-up phase"), and by testing for association between each component and biological endophenotypes, namely head circumference, serotonin blood levels, and global urinary peptide excretion rates ("biological correlation phase"). Four independent components were identified, namely "circadian & sensory dysfunction," "immune dysfunction," "neurodevelopmental delay," and "stereotypic behavior," together representing 74.5% of phenotypic variance in our sample. Marker variables in the latter three components are positively associated with macrocephaly, global peptiduria, and serotonin blood levels, respectively. These four components point toward at least four processes associated with autism, namely (I) a disruption of the circadian cycle associated with behavioral and sensory abnormalities, (II) dysreactive immune processes, surprisingly linked both to prenatal obstetric complications and to excessive postnatal body growth rates, (III) a generalized developmental delay, and (IV) an abnormal neural circuitry underlying stereotypies and early social behaviors.

Genetic Models of Serotonin (5‐HT) Depletion: What do They Tell Us About the Developmental Role of 5‐HT?

A large number of hyposerotonergic genetic models have been generated over the past few years. Serotonin (5-HT) depletion has been obtained via targeting of genes involved in 5-HT synthesis (Tph1 and Tph2), specification and determination of the 5-HT phenotype during development (GATA3, Pet1, and Lmx1b), and 5-HT storage or clearance (Vmat2 and SERT). Here we review these various models from a developmental perspective, beginning with a description of the sources of 5-HT during development. We then summarize the neurological and behavioral alterations that have been observed in the genetic hyposerotonergic models. Although these models appear to have normal brain development and do not exhibit any gross morphological defects, problems in somatic growth and physiological functions have been observed. Abnormal adult behavior is also seen, although whether it results from depletion of 5-HT during development or functional 5-HT deficiencies in adult life remains unclear. Evidence from these hyposerotonergic models suggests that the developing brain may not need 5-HT for the establishment of general organization and structure. However, central 5-HT appears to be necessary for postnatal body growth, maturation of respiratory and vegetative control, and possibly for the development of normal adult behavior.

Hepatocyte expression of serum response factor is essential for liver function, hepatocyte proliferation and survival, and postnatal body growth in mice #

Serum response factor (SRF) is a transcription factor that binds to a CarG box motif within the serum response element of genes that are expressed in response to mitogens. SRF plays essential roles in muscle and nervous system development; however, little is known about the role of SRF during liver growth and function. To examine the function of SRF in the liver, we generated mice in which the Srf gene was specifically disrupted in hepatocytes. The survival of mice lacking hepatic SRF activity was lower than that of control mice; moreover, surviving mutant mice had lower blood glucose and triglyceride levels compared with control mice. In addition, Srf(loxP/loxP)AlfpCre mice were smaller and had severely depressed levels of serum insulin-like growth factor 1 (IGF-1). Srf-deficient livers were also smaller than control livers, and liver cell proliferation and viability were compromised. Gene array analysis of SRF depleted livers revealed a reduction in many messenger RNAs, including those encoding components of the growth hormone/IGF-1 pathway, cyclins, several metabolic regulators, and cytochrome p450 enzymes. SRF is essential for hepatocyte proliferation and survival, liver function, and control of postnatal body growth by regulating hepatocyte gene expression.

Effects of maternal cold exposure and nutrient restriction on the ghrelin receptor, the GH–IGF axis, and metabolic regulation in the postnatal ovine liver

Maternal cold exposure of pregnant sheep promotes fetal growth, whereas nutrient restriction (NR) can reverse this effect. The present study was designed to establish whether cold exposure induced by winter shearing of the mother at 70 days gestation (term=147 days), with or without NR (induced by a 50% reduction in maternal food intake from 110 days gestation), has specific effects on mRNA abundance of hepatic genes related to growth and liver energy metabolism that could regulate postnatal body and liver growth. Measurements of hepatic gene expression for the GH secretagog receptor-1a (GHSR-1A), peroxisome proliferator-activated receptor (PPAR)alpha, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase activity together with glycogen content were made in the livers of offspring at 1 and 30 days of age. Maternal NR reduced liver mass at day 1, whereas offspring of cold-exposed mothers had larger livers at day 30 irrespective of maternal diet. Cold exposure resulted in the up-regulation of GHSR-1A mRNA abundance and reduced glucose-6-phosphatase activity at 1, but not 30 days of age, whereas IGF-II mRNA was decreased at 1 and 30 days. PPARalpha mRNA abundance was enhanced, while PEPCK was reduced in 30-day old offspring of cold-exposed mothers. NR caused reductions in IGF-I mRNA and, at 1-day postnatal age, down-regulated GHR, while, at 30 days, reduced GHSR-1A gene expression and hepatic glycogen content. In conclusion, we have shown that maternal cold exposure and NR have different effects on the hepatic GH-IGF and metabolic axis that may contribute to changes in liver growth over the first month of life.

Postnatal Body Growth Is Dependent on the Transcription Factors Signal Transducers and Activators of Transcription 5a/b in Muscle: A Role for Autocrine/Paracrine Insulin-Like Growth Factor I

The transcription factors signal transducers and activators of transcription (STAT)5a and STAT5b (STAT5) are essential mediators of many actions of GH, including transcription of the IGF-I gene. Here, we present evidence that skeletal muscle STAT5 is important for postnatal growth and suggest that this is conveyed by the production of localized IGF-I. To investigate the role of STAT5 signaling in skeletal muscle, mice with a skeletal-muscle-specific deletion of the Stat5a and Stat5b genes (Stat5MKO mice) were used. IGF-I mRNA levels were reduced by 60% in muscle tissue of these mice. Despite only a 15% decrease in circulating IGF-I, 8-wk-old male Stat5MKO mice displayed approximately 20% reduction in body weight that was accounted for by a reduction in lean mass. The skeletons of Stat5MKO mice were found to be smaller than controls, indicating the growth defect was not restricted to skeletal muscle. These results demonstrate an as yet unreported critical role for STAT5 in skeletal muscle for local IGF-I production and postnatal growth and suggest the skeletal muscle as a major site of GH action.

Influence of the hypogonadism (hgn) locus on female reproduction and ovarian development in an altered genetic background.

Background and Aims: The hypogonadic rat (hgn/hgn) shows male sterility controlled by a single recessive gene hgn. The hgn/hgn females detected by the presence of renal hypoplasia in the HGN inbred strain show a reduced fertility. Recently, the gene responsible for male hypogonadism was mapped on chromosome 10 by a linkage analysis using only male backcross progeny. Because backcross females could not be categorized as affected or normal because of variations in their renal sizes, we could not examine female fertility in the backcross progeny. In the present experiment, we examined whether the gene mapped on rat chromosome 10 has any influences on female reproduction and ovarian development. Methods: The assumptive hgn/hgn females were identified in the backcross progeny by microsatellite markers closely linked to the hgn locus. Postnatal body growth, the weights of reproductive organs, estrus cycle and ovarian histology were examined. In addition, backcross embryos were genotyped, and their body growth and ovarian development was examined. Results: The hgn/hgn females showed growth retardation, a short reproductive life and an abnormal ovarian histology as adults. Regarding embryonic development, hgn/hgn females showed body growth retardation and ovarian hypoplasia. Conclusion: The mutation of the hgn mapped on chromosome 10 causes not only male sterility but also female reduced fertility related to ovarian hypoplasia beyond the altered genetic background. (Reprod Med Biol 2006; 5: 227-234).