Enhanced GLUT4-Dependent Glucose Transport Relieves Nutrient Stress in Obese Mice Through Changes in Lipid and Amino Acid Metabolism

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...

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Published inDiabetes (New York, N.Y.) Vol. 65; no. 12; pp. 3585 - 3597
Main Authors Gurley, Jami M, Ilkayeva, Olga, Jackson, Robert M, Griesel, Beth A, White, Phillip, Matsuzaki, Satochi, Qaisar, Rizwan, Van Remmen, Holly, Humphries, Kenneth M, Newgard, Christopher B, Olson, Ann Louise
Format Journal Article
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Published United States American Diabetes Association 01.12.2016
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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.
AbstractList 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.
Author Qaisar, Rizwan
Ilkayeva, Olga
Jackson, Robert M
White, Phillip
Olson, Ann Louise
Matsuzaki, Satochi
Van Remmen, Holly
Griesel, Beth A
Gurley, Jami M
Humphries, Kenneth M
Newgard, Christopher B
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  organization: Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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  organization: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology and Medicine, Duke University, Durham, NC
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  surname: Olson
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  email: ann-olson@ouhsc.edu
  organization: Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK ann-olson@ouhsc.edu
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Snippet Impaired GLUT4-dependent glucose uptake is a contributing factor in the development of whole-body insulin resistance in obese patients and obese animal models....
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StartPage 3585
SubjectTerms Amino acids
Amino Acids - metabolism
Animals
Biological Transport - physiology
Blotting, Western
Carnitine O-Palmitoyltransferase - genetics
Carnitine O-Palmitoyltransferase - metabolism
Glucose
Glucose - metabolism
Glucose Transporter Type 4 - genetics
Glucose Transporter Type 4 - metabolism
Glycogen - metabolism
Humans
Insulin resistance
Lipid Metabolism - genetics
Lipid Metabolism - physiology
Male
Metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria - metabolism
Musculoskeletal system
Obesity
Obesity - genetics
Obesity - metabolism
Rodents
Triglycerides - metabolism
Title Enhanced GLUT4-Dependent Glucose Transport Relieves Nutrient Stress in Obese Mice Through Changes in Lipid and Amino Acid Metabolism
URI https://www.ncbi.nlm.nih.gov/pubmed/27679559
https://www.proquest.com/docview/1846271646
https://search.proquest.com/docview/1843911787
https://pubmed.ncbi.nlm.nih.gov/PMC5127250
Volume 65
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