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Maternal obesity reduces oxidative capacity in fetal skeletal muscle of Japanese macaques
Carrie E. McCurdy, … , Kevin L. Grove, Jacob E. Friedman
Carrie E. McCurdy, … , Kevin L. Grove, Jacob E. Friedman
Published October 6, 2016
Citation Information: JCI Insight. 2016;1(16):e86612. https://doi.org/10.1172/jci.insight.86612.
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Research Article Metabolism Muscle biology

Maternal obesity reduces oxidative capacity in fetal skeletal muscle of Japanese macaques

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Abstract

Maternal obesity is proposed to alter the programming of metabolic systems in the offspring, increasing the risk for developing metabolic diseases; however, the cellular mechanisms remain poorly understood. 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 fetal skeletal muscle metabolism studied in the early third trimester. We find that fetal muscle responds to Ob/WSD by upregulating fatty acid metabolism, mitochondrial complex activity, and metabolic switches (CPT-1, PDK4) that promote lipid utilization over glucose oxidation. Ob/WSD fetuses also had reduced mitochondrial content, diminished oxidative capacity, and lower mitochondrial efficiency in muscle. The decrease in oxidative capacity and glucose metabolism was persistent in primary myotubes from Ob/WSD fetuses despite no additional lipid-induced stress. Switching obese mothers to a healthy diet prior to pregnancy did not improve fetal muscle mitochondrial function. Lastly, while maternal WSD alone led only to intermediary changes in fetal muscle metabolism, it was sufficient to increase oxidative damage and cellular stress. Our findings suggest that maternal obesity or WSD, alone or in combination, leads to programmed decreases in oxidative metabolism in offspring muscle. These alterations may have important implications for future health.

Authors

Carrie E. McCurdy, Simon Schenk, Byron Hetrick, Julie Houck, Brian G. Drew, Spencer Kaye, Melanie Lashbrook, Bryan C. Bergman, Diana L. Takahashi, Tyler A. Dean, Travis Nemkov, Ilya Gertsman, Kirk C. Hansen, Andrew Philp, Andrea L. Hevener, Adam J. Chicco, Kjersti M. Aagaard, Kevin L. Grove, Jacob E. Friedman

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Figure 2

Maternal obesity combined with a Western-style diet (WSD) upregulates fatty acid metabolism in fetal muscle.

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Maternal obesity combined with a Western-style diet (WSD) upregulates fa...
Cellular lipids including (A) triglycerides, (B) fatty acids, and (C) phospholipids were extracted from fetal gastrocnemius (gastroc) and analyzed by mass spectrometry from male (M, circles) and female (F, triangles) offspring of lean/overweight dams that had only received control diet (Ln/CTR; n = 5–6 M, 6 F), Ln/WSD (n = 5 M, 5–6 F), and obese dams chronically fed a WSD (Ob/WSD; n = 6–12 M, 6–10 F) groups. Protein abundance for (D) CPT-1β, (G) VLCAD, (H) SCHAD, and (I) LDHα was measured by Western blot in fetal muscle from Ln/CTR (n = 5–7 M, 7 F), Ln/WSD (n = 6 M, 6–8 F), Ob/WSD (n = 11 M, 10–12 F). (F) Representative Western blots are shown for fatty acid transport and oxidation enzymes in male offspring. VLCAD was run in a separate gel from the other proteins listed. Data were adjusted to GAPDH. Gene expression of (E) PDK4, (J) PGC1A, and (K) SIRT1 was measured by qPCR and expressed relative to ribosomal protein S15 (RPS15) in fetal gastroc from offspring of Ln/CTR (n = 5–6 M, 8 F), Ln/WSD (n = 3 M, 3 F), Ob/WSD (n = 10 M, 8 F). All data were analyzed by 2-way ANOVA (maternal group × fetal sex) with post-hoc tests. P values for significant main effects are listed in each graph. Groups with the same letter are not significantly different from each other in post-hoc analysis. Individual data points and the group mean ± SEM are shown.

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