Maternal obesity in sheep impairs fetal hepatic respiratory chain capacity

Background: Changes in the nutritional environment in utero induced by maternal obesity (MO) lead to fetal metabolic dysfunction predisposing offspring to later-life metabolic diseases. Since mitochondria play a crucial role in hepatic metabolism and function, we hypothesized that MO prior to conception and throughout pregnancy programs fetal sheep liver mitochondrial phenotype.

Material and methods: Ewes ate an obesogenic diet (150% requirements; MO), or 100% requirements (CTR) from 60 d prior to conception. Fetal livers were removed at 0.9 gestation. We measured fetal liver mitochondrial DNA copy number, activity of superoxide dismutase, cathepsins B and D and selected proteins content, total phospholipids and cardiolipin and activity of mitochondrial respiratory chain complexes.

Results: A significant decrease in activities of mitochondrial complexes I, II-III and IV, but not aconitase, was observed in MO. In the antioxidant machinery there was a significant increase in activity of total superoxide dismutase (SOD) and SOD2 in MO. However, no differences were found regarding autophagy-related proteins content (p62, beclin-I, LC3-I, LC3-II and Lamp2A) and cathepsins B and D activities. A 21.5% decrease in total mitochondrial phospholipid was observed in MO.

Conclusions: The data indicate that MO impairs fetal hepatic mitochondrial oxidative capacity and affects total mitochondrial phospholipids content. In addition, MO affects the regulation of fetal liver redox pathways, sindicating metabolic adaptations to the higher fetal lipid environment. Consequences of in utero programming of fetal hepatic metabolism may persist and compromise mitochondrial bioenergetics in later life, and increase susceptibility to metabolic diseases.

Keywords: Maternal obesity; metabolic programming; mitochondrial bioenergetics; mitochondrial phospholipids; oxidative stress.