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  • br Discussion In the present

    2021-11-22


    Discussion In the present study, we have demonstrated the effect of a high-fat diet upon wild-type and glut3 pregestational female phenotype and shown that it leads to obesity due to an increase in white adipose tissue contributing to the overall fat mass. Despite this observed obesity along with an increase in plasma total cholesterol and high-density lipoprotein in ido1 inhibitor both genotypes, a reduction in plasma triglycerides with a genotype-specific differential change in free fatty acids was noted. These observations are unlike previous investigations in response to a high-fat diet, except that our studies were undertaken in young fertile female mice as opposed to a majority of prior studies in male mice [7], [27], [28], [29]. Another investigation conducted in prepregnant female and newborn rats previously revealed similar results as we noted in our present study [30], [31]. In fact, during pregestation, there is no increase in triglycerides in response to a high-fat diet, which was only seen to increase at E20 during pregnancy. Similarly, in the newborn born to a high-fat-fed rat, triglycerides were decreased. Thus, the response to a high-fat diet over an 8-week period during the prepregnant state as in our present study appears to relay sex-specific differences when compared with previous rat and mouse studies when collectively taken into consideration. We have previously shown that high murine maternal cholesterol concentrations in response to a Western diet upon an LDLR ido1 inhibitor were associated with a higher incidence of aortic atherosclerotic lesions in both the male and female offspring [32] despite normal cholesterol concentrations in the offspring per se. While we did not examine cholesterol levels during pregnancy in the present study, prepregnancy elevated plasma cholesterol levels can be extrapolated to persist during pregnancy. Pregestation cholesterol concentrations predict such an elevation during gestation and postgestation, especially when the high-fat diet is continued throughout pregnancy and furthermore during lactation. Although we detected increased high-density lipoprotein concentrations, the increasing incidence of atherosclerotic lesions in the offspring despite no change in the total cholesterol concentrations in the offspring reported previously [32] questions the protection afforded by maternal high-density lipoprotein concentrations on offspring's health. In keeping with the changes in body weight and fat mass, both genotypes reveal glucose intolerance in the high-fat-exposed groups. Hence, prepregnancy weight gain in response to a high-fat diet is associated with elevated basal glucose concentrations and glucose intolerance, a predictor of gestational diabetes mellitus. However, a key observation was that the female pregestational mice in both genotypes were not insulin resistant. Although our previous study employing glut3 male mice reared on a chow diet demonstrated obesity, glucose intolerance, insulin resistance and a fatty liver by 9–11 months of age, a similar phenotype was not seen in age-matched chow-reared female mice [23]. Our present observations in glut3 younger female mice on chow diet are similar to older female mice from our previous study [23]. The younger (~3 months old) glut3 pregestational female mice reared on a chow diet in our present study mimic their age- and sex-matched wild-type counterpart in this regard. This demonstrates that the female sex is protective in preventing obesity and its associated complications in the chow-reared glut3 genotype. Upon exposure to a high-fat diet, these glut3 pregestational 3-month-old female mice for the most part reflect their age- and sex-matched wild-type counterparts. Both wild-type and glut3 mice become obese during pregestation with increased white adipose tissue/fat mass, while all other organ weights remain unchanged. However, while the increase in abdominal white adipose tissue weight in response to HFD was similar among the two genotypes, total fat mass by NMR demonstrated a difference, with the wild type showing a greater increase (fourfold) than that of the glut3 (twofold) genotype. Reflecting this pregestational obesity, both wild-type and glut3 female mice also develop glucose intolerance, but while the wild-type mice remain insulin sensitive, the glut3 mice express a tendency toward relative insulin resistance.