The thrust of this proposal is to elucidate the regulation and interaction of carbohydrate and lipid metabolism in the liver and non-hepatic tissues, especially heart and skeletal muscle. Developments over the last grant period have cast doubt on traditional concepts of glucose homeostasis. In addition, intriguing aspects of the regulatory role of malonyl-CoA in fatty acid metabolism have come to light. Accordingly, two broad lines of investigation will be carried out. The first involves a study of the regulatory events initiating the conversion of catabolic metabolism to anabolic metabolism when fasted animals are refed. Three main questions will be posed: (1) what controls glucose-6-phosphate flow into glycogen or plasma glucose in fasting and its reversal? (2) What dictates whether glycogen is formed directly or indirectly (via lactate) from glucose? (3) What controls fructose-2, 6-bisphosphate levels in the liver after refeeding? The second series of experiments addresses the regulatory interaction between malonyl-CoA and carnitine palmitoyl-transferase I (CPT I), the rate limiting enzyme for fatty acid oxidation and ketogenesis. Again, three major questions will be asked: (1) is malonyl-CoA a physiologic regulator of fatty acid metabolism in non-hepatic tissues? (2) Are CPT I and CPT II different enzymes? (3) How does malonyl-CoA inhibit CPT I? Answers to these questions are important for an understanding of normal fuel metabolism and its derangements in disease states - particularly uncontrolled diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK018573-28
Application #
3226093
Study Section
(SSS)
Project Start
1975-06-01
Project End
1990-05-31
Budget Start
1989-06-01
Budget End
1990-05-31
Support Year
28
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Dobbins, Robert L; Malloy, Craig R (2003) Measuring in-vivo metabolism using nuclear magnetic resonance. Curr Opin Clin Nutr Metab Care 6:501-9
Brown, Nicholas F (2003) Expression, purification, and reconstitution of rat liver carnitine palmitoyltransferase I. Methods Mol Biol 228:281-301
Dobbins, Robert L; Szczepaniak, Lidia S; Zhang, Weiguo et al. (2003) Chemical sympathectomy alters regulation of body weight during prolonged ICV leptin infusion. Am J Physiol Endocrinol Metab 284:E778-87
Dobbins, Robert L; Szczepaniak, Lidia S; Myhill, Jeff et al. (2002) The composition of dietary fat directly influences glucose-stimulated insulin secretion in rats. Diabetes 51:1825-33
Dobbins, R L; Szczepaniak, L S; Bentley, B et al. (2001) Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes 50:123-30
Caserta, F; Tchkonia, T; Civelek, V N et al. (2001) Fat depot origin affects fatty acid handling in cultured rat and human preadipocytes. Am J Physiol Endocrinol Metab 280:E238-47
McGarry, J D (2001) Travels with carnitine palmitoyltransferase I: from liver to germ cell with stops in between. Biochem Soc Trans 29:241-5
Mulder, H; Lu, D; Finley 4th, J et al. (2001) Overexpression of a modified human malonyl-CoA decarboxylase blocks the glucose-induced increase in malonyl-CoA level but has no impact on insulin secretion in INS-1-derived (832/13) beta-cells. J Biol Chem 276:6479-84
Brown, N F; Mullur, R S; Subramanian, I et al. (2001) Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme. J Lipid Res 42:1134-42
McGarry, J D; Brown, N F (2000) Reconstitution of purified, active and malonyl-CoA-sensitive rat liver carnitine palmitoyltransferase I: relationship between membrane environment and malonyl-CoA sensitivity. Biochem J 349:179-87

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