Effects of maternal nutrient restriction, intrauterine growth restriction, and glucocorticoid exposure on phosphoenolpyruvate carboxykinase-1 expression in fetal baboon hepatocytes in vitro

Background: The objective of this study was to develop a cell culture system for fetal baboon hepatocytes and to test the hypotheses that (i) expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase-1 (PEPCK-1) is upregulated in hepatocytes isolated from fetuses of nutrient-restricted mothers (MNR) compared with ad libitum-fed controls (CTR), and (ii) glucocorticoids stimulate PEPCK-1 expression. Methods: Hepatocytes from 0.9G CTR and MNR fetuses were isolated and cultured. PEPCK-1 protein and mRNA levels in hepatocytes were determined by Western blot and quantitative PCR, respectively. Results: Fetuses of MNR mothers were intrauterine growth restricted (IUGR). Feasibility of culturing 0.9G fetal baboon hepatocytes was demonstrated. PEPCK-1 protein levels were increased in hepatocytes isolated from IUGR fetuses, and PEPCK-1 mRNA expression was stimulated by glucocorticoids in fetal hepatocytes. Conclusions: Cultured fetal baboon hepatocytes that retain their in vivo phenotype provide powerful in vitro tools to investigate mechanisms that regulate normal and programmed hepatic function. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Different levels of overnutrition and weight gain during pregnancy have differential effects on fetal growth and organ development

<p>Abstract</p> <p>Background</p> <p>Nearly 50% of U.S. women of child-bearing age are overweight or obese, conditions linked to offspring obesity and diabetes.</p> <p>Methods</p> <p>Utilizing the sheep, females were fed a highly palatable diet at two levels of overfeeding designed to induce different levels of maternal body weight increase and adiposity at conception, and from conception to midgestation. Fetal growth and organ development were then evaluated at midgestation in response to these two different levels of overfeeding. Ewes were fed to achieve: 1) normal weight gain (control, C), 2) overweight (125% of National Research Council [NRC] recommendations, OW125) or 3) obesity (150% of NRC recommendations, OB150) beginning 10 wks prior to breeding and through midgestation. Body fat % and insulin sensitivity were assessed at three points during the study: 1) diet initiation, 2) conception and 3) mid-gestation. Ewes were necropsied and fetuses recovered at mid-gestation (day 78).</p> <p>Results</p> <p>OB150 ewes had a higher % body fat than OW125 ewes prior to breeding (P = 0.03), but not at mid-gestation (P = 0.37). Insulin sensitivity decreased from diet initiation to mid-gestation (P = 0.04), and acute insulin response to glucose tended to be greater in OB150 ewes than C ewes (P = 0.09) and was greater than in OW125 ewes (P = 0.02). Fetal crown-rump length, thoracic and abdominal girths, and fetal perirenal fat were increased in the OW125 and OB150 versus C ewes at mid-gestation. However, only fetal heart, pancreas, and liver weights, as well as lipid content of fetal liver, were increased (P < 0.05) in OB150 ewes versus both C and OW125 ewes at midgestation.</p> <p>Conclusions</p> <p>These data demonstrate that different levels of overfeeding, resulting in differing levels of maternal weight gain and adiposity prior to and during pregnancy, lead to differential effects on fetal overgrowth and organ development.</p

Different Statistical Approaches to Characterization of Adipocyte Size in Offspring of Obese Rats: Effects of Maternal or Offspring Exercise Intervention

Adipocyte size (AS) shows asymmetric distribution related to current metabolic state, e.g., adipogenesis or lipolysis. We profiled AS distribution using different statistical approaches in offspring (F1) of control (C) and obese (MO) mothers (F0) with and without F0 or F1 exercise. Offspring from F0 exercise were designated CF0ex and MOF0ex. Exercised F1 of sedentary mothers were designated CF1ex and MOF1ex. F1 retroperitoneal fat cross-sectional AS was measured by median, cumulative distributions, data dispersion and extreme values based on gamma distribution modeling. F1 metabolic parameters: body weight, retroperitoneal fat, adiposity index (AI), serum leptin, triglycerides (TG) and insulin resistance index (IRI) were measured. Male and female F1 AS showed different cumulative distribution between C and MO (p &lt; 0.0001) therefore comparisons were performed among C, CF0ex and CF1ex groups and MO, MOF0ex and MOF1ex groups. MO AI was higher than C (p &lt; 0.05) and male MOF1ex AI lower than MO (p &lt; 0.05). Median AS was higher in male and female MO vs. C (p &lt; 0.05). Male and female MOF0ex and MOF1ex reduced median AS (p &lt; 0.05). Lower AS dispersion was observed in male CF1ex and MOF1ex vs. CF0ex and MOF0ex, respectively. MO reduced small and increased large adipocyte proportions vs. C (p &lt; 0.05); MOF0ex increased small and MOF1ex the proportion of large adipocytes vs. MO (p &lt; 0.05). MOF0ex reduced male IRI and female TG vs. MO (p &lt; 0.05). MOF1ex reduced male and female leptin (p &lt; 0.05); CF1ex reduced male leptin (p &lt; 0.05). Conclusions: several factors, diet, physical activity and gender modify AS distribution. Conventional AS distribution methods normally do not include analyzes of extreme, large and small adipocytes, which characterize different phenotypes. Maternal high fat diet affects F1 AS distribution, which was programmed during development. F0ex and F1ex have gender specific F1 beneficial effects. AS distribution characterization helps explain adipose tissue metabolic changes in different physiological conditions and will aid design of efficacious interventions to prevent and/or recuperate adverse developmental programming outcomes. Finally, precise identification of effects of specific interventions as exercise of F0 and/or F1 are needed to improve outcomes in obese women and their obesity prone offspring

The influence of long chain polyunsaturate supplementation on docosahexaenoic acid and arachidonic acid in baboon neonate central nervous system

BACKGROUND: Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are major components of the cerebral cortex and visual system, where they play a critical role in neural development. We quantitatively mapped fatty acids in 26 regions of the four-week-old breastfed baboon CNS, and studied the influence of dietary DHA and ARA supplementation and prematurity on CNS DHA and ARA concentrations. METHODS: Baboons were randomized into a breastfed (B) and four formula-fed groups: term, no DHA/ARA (T-); term, DHA/ARA supplemented (T+); preterm, no DHA/ARA (P-); preterm and DHA/ARA supplemented (P+). At four weeks adjusted age, brains were dissected and total fatty acids analyzed by gas chromatography and mass spectrometry. RESULTS: DHA and ARA are rich in many more structures than previously reported. They are most concentrated in structures local to the brain stem and diencephalon, particularly the basal ganglia, limbic regions, thalamus and midbrain, and comparatively lower in white matter. Dietary supplementation increased DHA in all structures but had little influence on ARA concentrations. Supplementation restored DHA concentrations to levels of breastfed neonates in all regions except the cerebral cortex and cerebellum. Prematurity per se did not exert a strong influence on DHA or ARA concentrations. CONCLUSION: 1) DHA and ARA are found in high concentration throughout the primate CNS, particularly in gray matter such as basal ganglia; 2) DHA concentrations drop across most CNS structures in neonates consuming formulas with no DHA, but ARA levels are relatively immune to ARA in the diet; 3) supplementation of infant formula is effective at restoring DHA concentration in structures other than the cerebral cortex. These results will be useful as a guide to future investigations of CNS function in the absence of dietary DHA and ARA

Physiological Correlates of Volunteering

We review research on physiological correlates of volunteering, a neglected but promising research field. Some of these correlates seem to be causal factors influencing volunteering. Volunteers tend to have better physical health, both self-reported and expert-assessed, better mental health, and perform better on cognitive tasks. Research thus far has rarely examined neurological, neurochemical, hormonal, and genetic correlates of volunteering to any significant extent, especially controlling for other factors as potential confounds. Evolutionary theory and behavioral genetic research suggest the importance of such physiological factors in humans. Basically, many aspects of social relationships and social activities have effects on health (e.g., Newman and Roberts 2013; Uchino 2004), as the widely used biopsychosocial (BPS) model suggests (Institute of Medicine 2001). Studies of formal volunteering (FV), charitable giving, and altruistic behavior suggest that physiological characteristics are related to volunteering, including specific genes (such as oxytocin receptor [OXTR] genes, Arginine vasopressin receptor [AVPR] genes, dopamine D4 receptor [DRD4] genes, and 5-HTTLPR). We recommend that future research on physiological factors be extended to non-Western populations, focusing specifically on volunteering, and differentiating between different forms and types of volunteering and civic participation

Differential Cerebral Cortex Transcriptomes of Baboon Neonates Consuming Moderate and High Docosahexaenoic Acid Formulas

BACKGROUND: Docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (ARA, 20:4n-6) are the major long chain polyunsaturated fatty acids (LCPUFA) of the central nervous system (CNS). These nutrients are present in most infant formulas at modest levels, intended to support visual and neural development. There are no investigations in primates of the biological consequences of dietary DHA at levels above those present in formulas but within normal breastmilk levels. METHODS AND FINDINGS: Twelve baboons were divided into three formula groups: Control, with no DHA-ARA; “L”, LCPUFA, with 0.33%DHA-0.67%ARA; “L3”, LCPUFA, with 1.00%DHA-0.67%ARA. All the samples are from the precentral gyrus of cerebral cortex brain regions. At 12 weeks of age, changes in gene expression were detected in 1,108 of 54,000 probe sets (2.05%), with most showing <2-fold change. Gene ontology analysis assigns them to diverse biological functions, notably lipid metabolism and transport, G-protein and signal transduction, development, visual perception, cytoskeleton, peptidases, stress response, transcription regulation, and 400 transcripts having no defined function. PLA2G6, a phospholipase recently associated with infantile neuroaxonal dystrophy, was downregulated in both LCPUFA groups. ELOVL5, a PUFA elongase, was the only LCPUFA biosynthetic enzyme that was differentially expressed. Mitochondrial fatty acid carrier, CPT2, was among several genes associated with mitochondrial fatty acid oxidation to be downregulated by high DHA, while the mitochondrial proton carrier, UCP2, was upregulated. TIMM8A, also known as deafness/dystonia peptide 1, was among several differentially expressed neural development genes. LUM and TIMP3, associated with corneal structure and age-related macular degeneration, respectively, were among visual perception genes influenced by LCPUFA. TIA1, a silencer of COX2 gene translation, is upregulated by high DHA. Ingenuity pathway analysis identified a highly significant nervous system network, with epidermal growth factor receptor (EGFR) as the outstanding interaction partner. CONCLUSIONS: These data indicate that LCPUFA concentrations within the normal range of human breastmilk induce global changes in gene expression across a wide array of processes, in addition to changes in visual and neural function normally associated with formula LCPUFA