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We recently reported insulin resistance in adult offspring of obese C57BL/6J mice. We have now evaluated whether parameters of skeletal muscle structure and function may play a role in insulin resistance in this model of developmental programming. Obesity was induced in female mice by feeding a highly palatable sugar and fat-rich diet for 6 wk prior to pregnancy, and during pregnancy and lactation. Offspring of obese dams were weaned onto standard laboratory chow. At 3 mo of age, skeletal muscle insulin signaling protein expression, mitochondrial electron transport chain activity (ETC), muscle fiber type, fiber density, and fiber cross-sectional area were compared with that of offspring of control dams weaned onto the chow diet. Female offspring of obese dams demonstrated decreased skeletal muscle expression of p110[beta], the catalytic subunit of PI3K (P < 0.01), as well as reduced Akt phosphorylation at Serine residue 473 compared with control offspring. Male offspring of obese dams demonstrated increased skeletal muscle Akt2 and PKC[zeta] expression (P < 0.01; P < 0.001, respectively). A decrease in mitochondrial-linked complex II-III was observed in male offspring of obese dams (P < 0.01), which was unrelated to CoQ deficiency. This was not observed in females. There were no differences in muscle fiber density between offspring of obese dams and control offspring in either sex. Sex-related alterations in key insulin-signaling proteins and in mitochondrial ETC may contribute to a state of insulin resistance in offspring of obese mice. maternal obesity; developmental programming; electron transport chain; insulin signaling; muscle metabolism

Background: It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental programming are not well characterized, and potential intervention strategies are poorly defined. Objectives: We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype. Design: A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed "recuperated"). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase-polymerase chain reaction. Results: Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 µm) than in controls (5 ± 0.5 mm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor a: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 µg/mL per mg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01). Conclusions: Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia. [ABSTRACT FROM AUTHOR]

Abstract: Studies in human and animals have demonstrated that nutritionally induced low birth-weight followed by rapid postnatal growth increases the risk of metabolic syndrome and cardiovascular disease. Although the mechanisms underlying such nutritional programming are not clearly defined, increased oxidative-stress leading to accelerated cellular aging has been proposed to play an important role. Using an established rodent model of low birth-weight and catch-up growth, we show here that post-weaning dietary supplementation with coenzyme Q10, a key component of the electron transport chain and a potent antioxidant rescued many of the detrimental effects of nutritional programming on cardiac aging. This included a reduction in nitrosative and oxidative-stress, telomere shortening, DNA damage, cellular senescence and apoptosis. These findings demonstrate the potential for postnatal antioxidant intervention to reverse deleterious phenotypes of developmental programming and therefore provide insight into a potential translatable therapy to prevent cardiovascular disease in at risk humans. [Copyright &y& Elsevier]

There is increasing evidence in humans that abnormal mitochondrial DNA (mtDNA) is associated with common degenerative disorders of the twenty-first century. mtDNA is exclusively female in origin and abnormalities in mtDNA can either be inherited, or generated de nova by adverse environmental factors that disturb mitochondrial DNA synthesis or destabilize mtDNA. The preimplantation period of development in mammals was thought to be relatively immune from environmentally induced changes to mtDNA, since no replication of mtDNA was thought to occur at this stage. This study demonstrates that there is a very short period of mtDNA synthesis immediately after fertilization, which can be affected by environmental stress. Adverse culture conditions during this phase of development could therefore alter the mitochondrial genome. with possible long-term consequences for the health of the offspring. The findings have relevance for all assisted reproduction programmes and for the rapidly emerging field of stem cell technologies. [ABSTRACT FROM AUTHOR]

Human preimplantation embryos at various stages of development have been analysed using the polymerase chain reaction to amplify a 680 base pair fragment of the β-globin gene. Successful amplification was achieved more frequently with DNA from intact embryos containing between one and 11 cells, single cumulus cells, oocytes which had failed to fertilize and polar bodies than from single blastomeres disaggregated from intact embryos and treated in an identical manner. The distribution of nuclei demonstrated using the nuclear chromophore diamino-phenyl-indole showed considerable inter-blastomere variation; however, no clear correlation between staining pattern and successful amplification was observed. The reason for the unreliable amplification of DNA from single blastomeres is unclear but this finding has important implications for preimplantation diagnosis of genetic disease. [ABSTRACT FROM PUBLISHER]

The first developmental lineage allocation during the generation of the mouse blastocyst is to outer trophoblast or to inner pluriblast (inner cell mass; ICM) cells. This allocation seems to be initiated at the 8-cell stage, when blastomeres polarise. Polarisation is followed by differentiative divisions at the subsequent two cleavage divisions to generate polar outer and non-polar inner 16- and 32-cells. The key events in polarisation are regulated post-translationally through a cell contact-mediated pathway, which imposes a heritable determinant-like organisation on the blastomere cortex. Two proteins in particular, E-cadherin and ezrin, are intimately involved in the generation and stabilisation of developmentally significant information. Transcriptional differences between lineages appear to follow and may coincide with the lineage commitment of cells.