It is now known that intramyocellular triglycerides (imcTG) content in skeletal muscle of obese adults is increased and this abnormality is associated with impaired glucose metabolism in the muscle. However, the pathways responsible for the increase and the link between the increased imcTG and insulin resistance have not been studied in detail. The objective of this application is to determine the factors and pathways that are responsible for the imcTG accumulation, and to determine whether the oxidation of imcTG fatty acids is also increased and, if so, whether it directly affects glucose metabolism. It is hypothesized that elevated plasma insulin and fatty acid levels, as commonly seen in human obesity, independently stimulate imcTG synthesis and synthesis is the primary pathway leading to the increased imcTG accumulation; and that a larger imcTG pool leads to accelerated imcTG oxidation thereby interfering with muscle glucose metabolism. To test the hypotheses, three specific aims will be pursued to answer following questions: 1) Is insulin an anabolic hormone stimulating imcTG synthesis? 2) Does elevated plasma fatty acid concentration increase imcTG synthesis by providing abundant precursors? 3) Is a larger imcTG pool associated with accelerated oxidation of imcTG fatty acids, and if so, how this affects muscle glucose metabolism? A new one-pool model will be applied to determine the rates of imcTG synthesis, turnover and oxidation directly (muscle biopsy) at controlled insulin and fatty acid levels in rats made obese by high fat feeding. The oxidation of imcTG fatty acids and muscle glucose uptake, glycolysis and glycogen synthesis will be determined using multiple tracers to determine the effect of imcTG oxidation on glucose metabolism. Stable isotopic tracers (13C) and mass spectrometry (GC/MS and isotope ratio MS) will be used to quantitate the kinetics. These studies are designed to answer the questions whether an enlarged imcTG is a chemical entity that imposes a negative effect on glucose metabolism, and whether plasma insulin and fatty acids are responsible for the increased imcTG, and if so, how. Thus, the proposed research will improve the understanding of the mechanism of insulin resistance and imcTG abnormalities in the obese rat that will benefit investigation of human obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060013-03
Application #
6613332
Study Section
Special Emphasis Panel (ZRG1-SSS-T (01))
Program Officer
Laughlin, Maren R
Project Start
2001-08-01
Project End
2006-05-31
Budget Start
2003-08-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$143,000
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Yu, Haoyong; Jia, Weiping; Guo, ZengKui (2014) Reducing Liver Fat by Low Carbohydrate Caloric Restriction Targets Hepatic Glucose Production in Non-Diabetic Obese Adults with Non-Alcoholic Fatty Liver Disease. J Clin Med 3:1050-63
Yu, Haoyong; Zhou, Dequan; Jia, Weiping et al. (2012) Locating the source of hyperglycemia: liver versus muscle. J Diabetes 4:30-6
Zhou, Dequan; Guo, ZengKui (2012) Intramyocellular lipids versus intramyocellular triglycerides. Magn Reson Med 67:297-8; author reply 299
Guo, Zengkui (2008) Intramyocellular lipids: maker vs. marker of insulin resistance. Med Hypotheses 70:625-9
Yan, Xuguang; Perez, Efren; Leid, Mark et al. (2007) Deuterium exchange and mass spectrometry reveal the interaction differences of two synthetic modulators of RXRalpha LBD. Protein Sci 16:2491-501
Guo, ZengKui (2007) Intramyocellular lipid kinetics and insulin resistance. Lipids Health Dis 6:18
Guo, Zk; Zhou, L (2006) Fatty acids inhibit intramyocellular triglyceride synthesis and turnover acutely in high fat-fed obese rats. Horm Metab Res 38:721-6
Guo, ZengKui; Yarasheski, Kevin; Jensen, Michael D (2006) High-precision isotopic analysis of palmitoylcarnitine by liquid chromatography/electrospray ionization ion-trap tandem mass spectrometry. Rapid Commun Mass Spectrom 20:3361-6
Guo, Zengkui; Zhou, Lianzhen; Jensen, Michael D (2006) Acute hyperinsulinemia inhibits intramyocellular triglyceride synthesis in high-fat-fed obese rats. J Lipid Res 47:2640-6
Yan, Xuguang; Deinzer, Max L; Schimerlik, Michael I et al. (2006) Investigation of ligand interactions with human RXRalpha by hydrogen/deuterium exchange and mass spectrometry. J Am Soc Mass Spectrom 17:1510-7

Showing the most recent 10 out of 17 publications