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.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.
Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
Jami M
JM
Gurley
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology and Medicine, Duke University, Durham, NC.
Olga
O
Ilkayeva
Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
Robert M
RM
Jackson
Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
Beth A
BA
Griesel
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology and Medicine, Duke University, Durham, NC.
Phillip
P
White
Oklahoma Medical Research Foundation, Metabolism and Aging Program, Oklahoma City, OK.
Satochi
S
Matsuzaki
Oklahoma Medical Research Foundation, Metabolism and Aging Program, Oklahoma City, OK.
Rizwan
R
Qaisar
Oklahoma Medical Research Foundation, Metabolism and Aging Program, Oklahoma City, OK.
Holly
H
Van Remmen
Oklahoma Medical Research Foundation, Metabolism and Aging Program, Oklahoma City, OK.
Kenneth M
http://orcid.org/0000-0002-6167-3175
KM
Humphries
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology and Medicine, Duke University, Durham, NC.
Christopher B
CB
Newgard
Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK ann-olson@ouhsc.edu.
Ann Louise
AL
Olson
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D015153:Blotting, Western; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
D000596:Amino Acids; D051275:Glucose Transporter Type 4; D014280:Triglycerides; D006003:Glycogen; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose
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