1. Enhanced GLUT4-Dependent Glucose Transport Relieves Nutrient Stress in Obese Mice Through Changes in Lipid and Amino Acid Metabolism
- Author
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Olga Ilkayeva, Christopher B. Newgard, Holly Van Remmen, Beth A. Griesel, Phillip J. White, Satochi Matsuzaki, Jami M. Gurley, Ann Louise Olson, Robert M. Jackson, Kenneth M. Humphries, and Rizwan Qaisar
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Transgene ,Glucose uptake ,Blotting, Western ,Mice, Transgenic ,Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Humans ,Obesity ,Amino Acids ,Triglycerides ,2. Zero hunger ,chemistry.chemical_classification ,Glucose Transporter Type 4 ,Carnitine O-Palmitoyltransferase ,Glucose transporter ,Skeletal muscle ,Fatty acid ,Biological Transport ,medicine.disease ,Lipid Metabolism ,Amino acid ,Mitochondria ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Metabolism ,Glucose ,Biochemistry ,chemistry ,biology.protein ,030217 neurology & neurosurgery ,GLUT4 ,Glycogen - Abstract
Impaired GLUT4-dependent glucose uptake is a contributing factor in the development of whole-body insulin resistance in obese patients and obese animal models. Previously, we demonstrated that transgenic mice engineered to express the human GLUT4 gene under the control of the human GLUT4 promoter (i.e., transgenic [TG] mice) are resistant to obesity-induced insulin resistance. A likely mechanism underlying increased insulin sensitivity is increased glucose uptake in skeletal muscle. The purpose of this study was to investigate the broader metabolic consequences of enhanced glucose uptake into muscle. We observed that the expression of several nuclear and mitochondrially encoded mitochondrial enzymes was decreased in TG mice but that mitochondrial number, size, and fatty acid respiration rates were unchanged. Interestingly, both pyruvate and glutamate respiration rates were decreased in TG mice. Metabolomics analyses of skeletal muscle samples revealed that increased GLUT4 transgene expression was associated with decreased levels of some tricarboxylic acid intermediates and amino acids, whereas the levels of several glucogenic amino acids were elevated. Furthermore, fasting acyl carnitines in obese TG mice were decreased, indicating that increased GLUT4-dependent glucose flux decreases nutrient stress by altering lipid and amino acid metabolism in skeletal muscle.
- Published
- 2016