A high fat maternal diet during the pregestation period and

A high-fat maternal diet during the pregestation period and extending throughout gestation (including the period of conception) has the propensity of affecting early embryonic development and placentation. Previous investigations have revealed that the preimplantation embryos are generally exposed to a low-oxygen environment when they enter the uterus [43], [44]. In addition, maternal obesity is associated with concomitant maternal hyperglycemia [45], [46]. However the preimplantation blastocysts in response to maternal diabetes generally experience relatively low glucose conditions in the immediate intrauterine environment in response to a reduction in glucose transporters (particularly Glut1 and Glut3). Both these conditions of hypoxia and low glucose can disarm mitochondrial metabolism, thereby triggering congenital malformations characteristic of preexisting maternal obesity/diabetes mellitus [26], [45], [46], [47]. To mimic these early intrauterine situations experienced by the preimplantation embryos of maternal obesity with glucose intolerance, we engaged both wild-type and glut3 embryonic stem PMX 205 receptor and recreated conditions of low glucose, hypoxia and inhibition of mitochondrial complex IV respiratory electron chain (cytochrome c oxidase) in vitro and observed a reduction in Glut3, while adequate compensation by Glut1 protein concentrations was not seen in response to either hypoxia or cytochrome C oxidase inhibition. In contrast, low glucose alone enhanced Glut3 protein which attempted to compensate for the reduction in glucose uptake encountered early mainly in wild type, with such increase being compromised in the glut3 ES cells. While these observations may not relate directly to the observations during late gestation in placental Glut3 and Glut1 concentrations, at both stages, one in early embryonic stem cells and the other in late gestation placentas reveal changes in Glut3 rather than in Glut1 protein concentrations, that mediate the effect of glucose on the developing embryo/fetus. Further, it lends support to the importance of Glut3 in embryonic cellular proliferation and growth, perhaps being the underlying mechanism contributing toward fetal growth as well. In the face of such changes, only a trend toward a diminution in placental SNAT2 and LAT2 protein concentrations occurred primarily in the high-fat-exposed glut3 genotype, suggesting the possibility of amino acid deficiencies in the developing fetus, further perpetuating aberrancy in the fetal–placental unit. Our previous studies in mice exposed to a Western diet revealed maternal amino acid deficiencies [32]. In conclusion, we have demonstrated the development of obesity and glucose intolerance in pregestational young female mice when fed a high-fat diet. This perturbed metabolic milieu induces elevated placental FAT/CD36 and Glut1 protein concentrations in wild-type and glut3 mice, while a compensatory added increase in Glut3 protein concentrations is predominantly seen only in the glut3 genotype. These placental changes are associated with birth weight changes and subsequent weight gain seen during the suckling phase. Further, mimicking the hypoxic and low glucose intrauterine conditions encountered, in response to maternal high-fat/glucose intolerance/hyperglycemia conditions, by the compacted preimplantation embryos, we determined changes demonstrating dramatic reduction in Glut3 with an inadequate compensation by Glut1. These changes in glucose transporter isoforms, ultimately affect glucose uptake and survival of these cells. Our present investigations demonstrate placental macronutrient transporter mechanisms underlying the connection between maternal dietary exposure and the offspring's immediate health. These mechanisms have the propensity of influencing the offspring's long term outcome by shaping their adult phenotype.
Acknowledgments This work was supported by National Institutes of HealthHD-41230 and HD-81206 (to S.U.D.).