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JCI Insight. 2016 Oct 6;1(16):e86612. doi: 10.1172/jci.insight.86612.

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

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Department of Human Physiology, University of Oregon, Eugene, Oregon, USA.
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Orthopaedic Surgery, University of California, San Diego, La Jolla, California, USA.
David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, University of California, Los Angeles, Los Angeles, California, USA.
Diabetes and Dyslipidaemia Laboratory, Baker IDI Heart and Diabetes Institute, Prahran, Victoria, Australia.
Departments of Health and Exercise Science and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA.
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Beaverton, Oregon, USA.
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
School of Sport Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
Novo Nordisk Research Center, Seattle, Washington, USA.


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.

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