Lipotoxicity in obese pregnancy and its potential role in adverse pregnancy outcome and obesity in the offspring

Abstract

Increasing maternal obesity is a challenge that has an impact on all aspects of female reproduction. Lean and obese pregnant women gain similar fat mass, but lean women store fat in the lower-body compartment and obese women in central compartments. In the non-pregnant, central storage of fat is associated with adipocyte hypertrophy and represents a failure to adequately store excess fatty acids, resulting in metabolic dysregulation and ectopic fat accumulation (lipotoxicity). Obese pregnancy is associated with exaggerated metabolic adaptation, endothelial dysfunction and increased risk of adverse pregnancy outcome. We hypothesize that the preferential storage of fat in central rather than 'safer' lower-body depots in obese pregnancy leads to lipotoxicity. The combination of excess fatty acids and oxidative stress leads to the production of oxidized lipids, which can be cytotoxic and influence gene expression by acting as ligands for nuclear receptors. Lipid excess and oxidative stress provoke endothelial dysfunction. Oxidized lipids can inhibit trophoblast invasion and influence placental development, lipid metabolism and transport and can also affect fetal developmental pathways. As lipotoxicity has the capability of influencing both maternal endothelial function and placental function, it may link maternal obesity and placentally related adverse pregnancy outcomes such as miscarriage and pre-eclampsia. The combination of excess/altered lipid nutrient supply, suboptimal in utero metabolic environment and alterations in placental gene expression, inflammation and metabolism may also induce obesity in the offspring.

Figure 1. Fatty acid metabolism in pregnancy

A central fat accumulation during pregnancy leads to fatty acid overspill from adipose depots and lipotoxicity. Lipotoxic effects include maternal endothelial dysfunction, decreased trophoblast invasion and altered placental metabolism. These may result in adverse pregnancy outcome (such as pre-eclampsia or miscarriage) and programming of obesity in the offspring. A lower-body fat accumulation allows ‘safe’ storage of fatty acids and a normal metabolic and physiological adaptation to pregnancy with appropriate nutrient transfer to the offspring. TG, triacylglycerol.