Proceedings of The Physiological Society

Mitochondria: Form and function (London, UK) (2017) Proc Physiol Soc 38, SA13

Research Symposium

The Effect of Maternal Diet & Obesity in Pregnancy on Mitochondrial Function in the Offspring

C. McCurdy1

1. University of Oregon, Eugene, Oregon, United States.


Maternal obesity and/or a poor nutritional diet during pregnancy is proposed to alter the programming of metabolic systems in the offspring, increasing the risk for developing metabolic diseases; however, the cellular mechanisms are still relatively unknown. Here, we used a nonhuman primate model to examine the impact of a maternal Western-style diet (WSD) alone, or in combination with obesity (Ob/WSD), on offspring skeletal muscle metabolism studied in early third trimester fetus and in lean juvenile (peripubertal) offspring at 3 years of age. We also tested the benefits of a healthy diet intervention initiated either at the start of pregnancy in obese dams or after weaning in juvenile offspring on offspring metabolic outcomes. Group-housed adult Japanese macaques were fed a control (CTR) or WSD for at least two years prior to the start of the study. A subset of obese dams that had been chronically fed WSD were switched to the healthy CTR diet at the start of pregnancy (Ob/DR). Pregnancies were terminated at gestational day 130/165 and fetal muscles collected (Ln/CTR, n=24; Ln/WSD, n=17; Ob/WSD, n=26; Ob/DR, n=6). A second cohort of offspring from Ln and Ob dams were taken to term, weaned at 7 months, and fed either the same maternal diet or switched to a the opposite diet (n=6-8). Substrate utilization and respiratory capacity were measured in permeabilized muscle fiber bundles (PMFBs) from fetal and juvenile muscle by high resolution respirometry (O2K, Oroboros). Data were analyzed by 1-way ANOVA in fetal muscle and 2-way ANOVA in juvenile muscle (maternal diet x postweaning diet). We find that fetal muscle adapts to maternal Ob/WSD by down-regulating glucose utilization and enhancing the capacity for fatty acid oxidation. Specifically, there was an increase in very-long-chain acyl-CoA dehydrogenase (VLCAD; 50%), carnitine palmitoyltransferase 1β abundance (CPT1β; 2-fold) and pyruvate dehydrogenase kinase 4 (PDK4; 2-fold) expression in Ob/WSD compared to Ln/CTR (P<0.01). Mitochondrial complex (C)-I and C-IV activities were also increased 2- and 3-fold in fetal muscle of Ob/WSD vs. Ln/CTR despite a decrease in markers of mitochondrial content. Muscle triglyceride accumulation was reduced by 50% in Ob/WSD (P<0.0001). Although, fetal muscle from Ln/WSD showed only intermediary changes in metabolic markers, maternal WSD alone was sufficient to increase oxidative damage (TBARs) and expression of markers of cellular stress (Gadd45, UCP2/3, SIRT1). In fetal PMFB, total oxidative capacity (20% lower), uncoupled ETS capacity (28%) and ETS coupling efficiency (15%) were significantly lower in Ob/WSD compared to Ln/CTR using non-lipid substrates (P<0.0001); addition of palmitoylcarnitine partially restored the decrease in oxidative capacity corroborating molecular data for increased lipid utilization. Switching obese dams to healthy diet during pregnancy further reduced both lipid and non-lipid oxidative metabolism and mitochondrial efficiency in PMFBs from fetal Ob/DR compared to Ob/WSD. Despite increased lipid utilization in fetal muscle, in PMFB of juvenile offspring (36 months) from Ln/WSD, there was an ~80% decrease in fatty acid oxidation (interaction; P<0.0001) and CI-linked oxidative capacity (interaction; P=0.01) independent of post-weaning diet. A similar decrease in fatty acid oxidation (but not CI- or total oxidative capacity) was also found in PMFB from offspring of Ln/CTR dams fed a post-weaning WSD. There was no effect of maternal WSD or post-weaning WSD on non-lipid oxidative metabolism or in citrate synthase activity in juvenile muscle. Maternal obesity/WSD leads to an early up-regulation in lipid oxidation and increased cellular stress in fetal muscle. These fetal adaptations likely contribute to the decrease in lipid oxidative metabolism in juvenile muscle and may increase the susceptibility to metabolic diseases in this population. Lastly, in these cohorts, we find that a healthy diet intervention alone, initiated in an obese pregnancy or at weaning, was insufficient to fully reverse the effects of maternal obesity or WSD, respectively on offspring mitochondrial metabolism.

Where applicable, experiments conform with Society ethical requirements