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Altered tricarboxylic acid cycle flux in primary myotubes from severely obese humans
Journal article   Open access   Peer reviewed

Altered tricarboxylic acid cycle flux in primary myotubes from severely obese humans

Kai Zou, J Matthew Hinkley, Sanghee Park, Donghai Zheng, Terry E Jones, Walter J Pories, Pamela J Hornby, James Lenhard, G Lynis Dohm and Joseph A Houmard
International journal of obesity (2005), v 43(4), pp 895-905
01 Apr 2019
DOI: https://doi.org/10.1038/s41366-018-0137-7
PMID: 29892037
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://figshare.com/articles/journal_contribution/Altered_tricarboxylic_acid_cycle_flux_in_primary_myotubes_from_severely_obese_humans/7813856View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open

Abstract

Adult Carbohydrate Metabolism - physiology Cells, Cultured - physiology Citric Acid Cycle - physiology Female Glycogen - metabolism Glycolysis - physiology Humans Male Muscle Fibers, Skeletal - metabolism Muscle Fibers, Skeletal - pathology Obesity, Morbid - metabolism Obesity, Morbid - physiopathology Primary Cell Culture Tricarboxylic Acids - metabolism
The partitioning of glucose toward glycolytic end products rather than glucose oxidation and glycogen storage is evident in skeletal muscle with severe obesity and type 2 diabetes. The purpose of the present study was to determine the possible mechanism by which severe obesity alters insulin-mediated glucose partitioning in human skeletal muscle. Primary human skeletal muscle cells (HSkMC) were isolated from lean (BMI = 23.6 ± 2.6 kg/m , n = 9) and severely obese (BMI = 48.8 ± 1.9 kg/m , n = 8) female subjects. Glucose oxidation, glycogen synthesis, non-oxidized glycolysis, pyruvate oxidation, and targeted TCA cycle metabolomics were examined in differentiated myotubes under basal and insulin-stimulated conditions. Myotubes derived from severely obese subjects exhibited attenuated response of glycogen synthesis (20.3%; 95% CI [4.7, 28.8]; P = 0.017) and glucose oxidation (5.6%; 95% CI [0.3, 8.6]; P = 0.046) with a concomitant greater increase (23.8%; 95% CI [5.7, 47.8]; P = 0.004) in non-oxidized glycolytic end products with insulin stimulation in comparison to the lean group (34.2% [24.9, 45.1]; 13.1% [8.6, 16.4], and 2.9% [-4.1, 12.2], respectively). These obesity-related alterations in glucose partitioning appeared to be linked with reduced TCA cycle flux, as 2-[ C]-pyruvate oxidation (358.4 pmol/mg protein/min [303.7, 432.9] vs. lean 439.2 pmol/mg protein/min [393.6, 463.1]; P = 0.013) along with several TCA cycle intermediates, were suppressed in the skeletal muscle of severely obese individuals. These data suggest that with severe obesity the partitioning of glucose toward anaerobic glycolysis in response to insulin is a resilient characteristic of human skeletal muscle. This altered glucose partitioning appeared to be due, at least in part, to a reduction in TCA cycle flux.

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Web of Science research areas
Endocrinology & Metabolism
Nutrition & Dietetics
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