Loss of stearoyl-CoA desaturase 1 inhibits fatty acid oxidation and increases glucose utilization in the heart

• Published in: American journal of physiology: endocrinology and metabolism 2008-02, Vol.294 (2), p.E357-E364
• Main Authors: Dobrzyn, Pawel, Sampath, Harini, Dobrzyn, Agnieszka, Miyazaki, Makoto, Ntambi, James M
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Carnitine O-Palmitoyltransferase - metabolism; Echocardiography; Fatty acids; Fatty Acids - metabolism; Glucose; Glucose - metabolism; Heart; Heart - physiology; Insulin; Insulin - physiology; Lipid Metabolism - physiology; Male; Mice; Mice, Knockout; Microsomes - enzymology; Microsomes - metabolism; Myocardium - metabolism; Oxidation; Oxidation-Reduction; Palmitates - metabolism; PPAR alpha - metabolism; Proteins; RNA - biosynthesis; RNA - isolation & purification; Signal Transduction - physiology; Stearoyl-CoA Desaturase - deficiency; Stearoyl-CoA Desaturase - genetics; Stearoyl-CoA Desaturase - physiology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00471.2007

1 Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Warsaw, Poland; and Departments of 2 Nutritional Sciences and 3 Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin Submitted 20 July 2007 ; accepted in final form 26 November 2007 Stearoyl-CoA desaturase (SCD) is a lipogenic enzyme that catalyzes the synthesis of monounsaturated fatty acids (FA). SCD1 deficiency activates metabolic pathways that promote FA β-oxidation and decrease lipogenesis in liver. In the present study, we show that FA transport and oxidation are decreased, whereas glucose uptake and oxidation are increased in the heart of SCD1 –/– mice. Protein levels of FA transport proteins such as FA translocase/CD36 and FA transport protein as well as activity of carnitine palmitoyltransferase 1, the rate-limiting enzyme for mitochondrial fat oxidation, were significantly lower in the heart of SCD1 –/– mice compared with SCD1 +/+ mice. Consequently, the rate of palmitoyl-CoA oxidation was decreased significantly in the heart of SCD1 –/– mice. mRNA levels of peroxisome proliferator-activated receptor- , a key transcription factor controlling genes of FA oxidation, were significantly reduced in SCD1 –/– mice. Phosphorylation of insulin receptor substrate-1 (IRS-1) and the association of p85 subunit of phosphatidylinositol 3-kinase with IRS-1 were significantly higher under both basal and insulin-stimulated conditions in SCD1 –/– hearts. This increased insulin sensitivity translated to a 1.8-fold greater 2-deoxyglucose uptake and 2-fold higher rate of glucose oxidation in the myocardium compared with SCD1 +/+ counterparts. The results suggest that SCD1 deficiency causes a shift in cardiac substrate utilization from FA to glucose by upregulating insulin signaling, decreasing FA availability, and reducing expression of FA oxidation genes in the heart. This increase in cardiac insulin sensitivity and glucose utilization due to SCD1 deficiency could prove therapeutic in pathological conditions such as obesity that are characterized by skewed cardiac substrate utilization. insulin signaling; fatty acid transport proteins; carnitine palmitoyltransferase 1; peroxisome proliferator-activated receptor Address for reprint requests and other correspondence: J. M. Ntambi, Dept. of Biochemistry, Univ. of Wisconsin, 433 Babcock Drive, Madison, WI 53706 (e-mail: ntambi{at}biochem.wisc.edu )