entacapone Unlike our present results in week old months fem

Unlike our present results in 4–12-week-old (~1–3 months) females, where a high-fat-diet-induced increase in body weight was evident, Schmidt et al. exposed male glut3 mice to a similar high-fat diet (60% kilocalories from fat) and observed no change in body weight, plasma glucose or insulin concentrations from 3 to 12 weeks of age [33]. Thus, on the surface, it appears that even at an early young adult stage, phenotypic sexual dimorphism exists in high-fat-fed glut3 mice which is opposite to what was seen previously in older glut3 mice reared on a chow diet [23] or even the age-matched high-fat-exposed pregestational glut3 females expressing increased body weight while the males remain resistant. However, unlike our present investigation, Schmidt et al. did not assess the fat mass or glucose tolerance in their 3-month-old high-fat-fed glut3 male mice [33]. Therefore, it is hard to say whether adiposity and glucose intolerance would have been detected in their high-fat-fed glut3 male mice similar to our present findings in female glut3 mice. All gestational high-fat dietary exposure studies have revealed that the offspring is born with a reduction in birth weight [9], [34], [35]. In our present investigation, we also observed such a decrease in birth weight of the offspring born to high-fat-exposed wild-type mice. It has been reasoned that such a reduction in birth weight is related to white adipose tissue development occurring postnatally rather than during the fetal stage [36], [37] along with an increase in transplacental fatty entacapone and/or glucose transport at the expense of amino acid transport [38], [39], [40], a reduction in the latter compromising fetal growth [19], [21], [41]. In contrast to the wild-type mice, an increase in the birth weight of the high-fat-exposed glut3 offspring was observed. While the wild-type high-fat-fed offspring's body weight caught up by PN21 with its chow-fed counterpart in males and females, the body weight of the glut3 male and female offspring exposed to a high-fat diet surpassed the wild-type high-fat-fed counterpart to be significantly higher than even its genotypic comparator exposed to chow diet. This increase may be related to a higher birth weight and intrauterine exposure to a relatively insulin-resistant maternal metabolic environment. Alternately, the in utero fetal growth may have occurred at the expense of building maternal total fat mass as seen in HFD-exposed glut3 female mice NMR studies (only twofold increase vs. the fourfold seen in wt mice). Based on these unique phenotypic observations in the pregestational females and the offspring born to them, we reasoned that placental transport mechanisms may underlie some of these genotype-specific effects in the offspring. To this end, we examined all three macronutrient transporter protein isoforms that are predominantly expressed in the late gestation placenta. We chose late gestation because most of the fetal growth occurs during late gestation. Our experiments revealed that maternal high-fat diet led to a trend in down-regulating placental FATP1 with no change in FATP4 in both genotypes. In contrast, an upregulation of placental FAT/CD36 particularly in the wild-type genotype may contribute to the observed trend toward a reduction in circulating free fatty acids in pregestational extrapolated to the gestational state. Further paralleling the reduction in free fatty acids, a reduction in circulating triglyceride concentrations was also encountered in the high-fat-exposed pregestational wild-type mice [30], [31]. In contrast, despite a trending increase in FAT/CD36 (although not significant) concentrations in the high-fat-exposed glut3 placentas, no change in circulating free fatty acids was encountered. These proteins are membrane-bound and responsible for placental long-chain fatty acid uptake toward mediating fetal growth and adiposity. An increase in placental Glut1 but not Glut3 was observed in wild-type mice placed on a high-fat diet. Previous investigations in C57/BL6 mice revealed an increase in placental glucose transport paralleling the change in Glut1 [5], [42]. However, our previous investigations in glut1 mice demonstrated no effect on transplacental glucose transport, supporting no major role for placental Glut1 in mediating glucose transport from mother to fetus (Ganguly, Touma et al. 2016). In contrast to our present observations in wild-type mice, an increase in both the placental glucose transporter isoforms, namely, Glut1 and Glut3, is suggestive of even further compensation with increased intraplacental and thereby transplacental glucose transport to the developing glut3 fetus. This may explain why the glut3 offspring exposed to a high-fat diet prenatally and during gestation expressed a higher birth weight (at the expense of building maternal fat mass) than the age-matched wild-type counterpart. Further continued exposure to a high-fat diet during lactation leads to a further increase in weight gain in the glut3 genotype beyond the same genotype being raised on a chow diet. In contrast, the lower-birth-weight high-fat-exposed wild-type neonatal mice catch up to those reared on chow diet by PN21 prior to weaning. These observations collectively raised the question as to whether a reduction in the Glut3 protein adversely affected glucose uptake and growth in embryonic cells and, if so, how were certain stressful situations encountered by the preimplantation embryos at conception (e.g., low glucose and hypoxia) handled in the presence of reduced Glut3.