1. Investigación

I. During the first two thirds of gestation, coinciding with a minimal accretion by the conceptus, the mother is in an anabolic state which is supported by her hyperphagia and the more efficient conservation of exogenous nutrients when she eats. During this phase maternal fat deposits are accumulated thanks to the enhancement in adipose tissue lipogenic and glycerolgenic activity. In contrast, in the latter part of gestation, the rapid fetal growth is sustained by the intense transfer of nutrients from maternal circulation. 2. Glucose is quantitatively the most abundant of the several substrates that cross the placenta and despite increased maternal gluconeogenesis this transfer is responsible for the maternal tendency to hypoglycemia. This causes a switch to a net catabolic state which is especially evident in the net breakdown of fat depots. 3. Enhanced release of adipose tissue Iipolytic products, free fatty acids (FFA) and glycerol, facilitates the liver synthesis of triglycerides and their later release into circulation associated to very low-density lipoprotein (VLDL). Glycerol is also used as an important gluconeogenic substrate and FF As are broken down through 13-oxidation for ketone body synthesis. Flow through these pathways becomes increased when food is withheld and this actively contributes to the availability of fuels to the fetus which becomes partially preserved from maternal metabolic insult. Increased liver production of VLDL-triglycerides and decreased extrahepatic lipoprotein lipase contribute to exaggerated maternal hypertriglyceridemia which, besides being a floating metabolic reserve for emergency conditions such as starvation, constitutes an essential substrate for milk synthesis around parturition in preparation for lactation. 4. While the maternal anabolic tendencies found during the first two-thirds of gestation seem to be facilitated by hyperinsulinemia in the presence of a normal responsiveness to the hormone, it is proposed that most of the metabolic changes taking place during the last third of gestation seem to be caused by the insulin-resistant state which is consistently present at this stage, since its reversion caused by sustained exaggerated hyperinsulinemia also reverts several of these metabolic adaptations.

The mechanism that induces maternal hypertriglyceridemia in late normal pregnancy, and its physiologic significance are reviewed as a model of the effects of sex steroids on lipoprotein metabolism. In the pregnant rat, maternal carcass fat content progressively increases up to day 19 of gestation, then declines at day 21. The decline may be explained by the augmented lipolytic activity in adipose tissue that is seen in late pregnancy in the rat. This change causes maternal circulating free fatty acids and glycerol levels to rise. Although the liver is the main receptor organ for these metabolites, liver triglyceride content is reduced. Circulating triglycerides and very-low-density lipoprotein (VLDL)-triglyceride levels are highly augmented in the pregnant rat, indicating that liver-synthesized triglycerides are rapidly released into the circulation. Similar increments in circulating VLDL-triglycerides are seen in pregnant women during the third trimester of gestation. This increase is coincident with a decrease in plasma postheparin lipoprotein lipase activity, indicating a reduced removal of circulating triglycerides by maternal tissues or a redistribution in their use among the different tissues. During late gestation in the rat, tissue lipoprotein lipase activity varies in different directions; it decreases in adipose tissue, the liver, and to a smaller extent the heart, but increases in placental and mammary gland tissue. These changes play an important role in the fate of circulating triglycerides, which are diverted from uptake by adipose tissue to uptake by the mammary gland for milk synthesis, and probably by the placenta for hydrolysis and transfer of released nonesterified fatty acids to the fetus. After 24 hours of starvation, lipoprotein lipase activity in the liver greatly increases in the rat in late pregnancy; this change is not seen in virgin animals. This alteration is similar to that seen in liver triglyceride content and plasma ketone body concentration in the fasted pregnant rat. In the fasting condition during late gestation, heightened lipoprotein lipase activity is the proposed mechanism through which the liver becomes an acceptor of circulating triglycerides, allowing their use as ketogenic substrates, so that both maternal and fetal tissues may indirectly benefit from maternal hypertriglyceridemia. Changes in the magnitude and direction of lipoprotein lipase activity in different tissues during gestation actively contribute both to the development of hypertriglyceridemia and to the metabolic fate of circulating triglycerides. Any deviation in these metabolic adaptations occurring in the human mother may have consequences that modify her lipoprotein profile, even postpartum. Hormone-induced changes in pregnancy mirror those seen with oral contraceptive steroids and provide a teleologic rationale for the lipoprotein changes induced by sex steroids.