Gene expression profiling in skeletal muscle of Zucker diabetic fatty rats: implications for a role of stearoyl-CoA desaturase 1 in insulin resistance

• Published in: Diabetologia 2005-12, Vol.48 (12), p.2622-2630
• Main Authors: Voss, M. D, Beha, A, Tennagels, N, Tschank, G, Herling, A. W, Quint, M, Gerl, M, Metz-Weidmann, C, Haun, G, Korn, M
• Format: Article
• Language: English
• Subjects: Acyl Coenzyme A - metabolism; Affymetrix; Animals; Biological and medical sciences; CD36 Antigens - analysis; CD36 Antigens - genetics; CD36 Antigens - physiology; Chromatography, High Pressure Liquid; diabetes; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation; Glucose - metabolism; Glucose - pharmacology; Insulin - physiology; insulin resistance; Insulin Resistance - genetics; Insulin Resistance - physiology; Lipid Metabolism - genetics; Male; Medical sciences; Muscle, Skeletal - chemistry; Muscle, Skeletal - enzymology; Muscle, Skeletal - metabolism; Oligonucleotide Array Sequence Analysis; Palmitates - pharmacology; Palmitoyl Coenzyme A - analysis; Palmitoyl Coenzyme A - genetics; Palmitoyl Coenzyme A - physiology; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; SCD1; skeletal muscle; stearoyl-CoA desaturase; Stearoyl-CoA Desaturase - genetics; Stearoyl-CoA Desaturase - metabolism; Striated muscle. Tendons; Vertebrates: osteoarticular system, musculoskeletal system; ZDF rat
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-005-0025-2

Aims/hypothesis Insulin resistance in skeletal muscle is a hallmark of type 2 diabetes. Therefore, we sought to identify and validate genes involved in the development of insulin resistance in skeletal muscle. Materials Differentially regulated genes in skeletal muscle of male obese insulin-resistant, and lean insulin-sensitive Zucker diabetic fatty (ZDF) rats were determined using Affymetrix microarrays. Based on these data, various aspects of glucose disposal, insulin signalling and fatty acid composition were analysed in a muscle cell line overexpressing stearoyl-CoA desaturase 1 (SCD1). Results Gene expression profiling in insulin-resistant skeletal muscle revealed the most pronounced changes in gene expression for genes involved in lipid metabolism. Among these, Scd1 showed increased expression in insulin-resistant animals, correlating with increased amounts of palmitoleoyl-CoA. This was further investigated in a muscle cell line that overexpressed SCD1 and accumulated lipids, revealing impairments of glucose uptake and of different steps of the insulin signalling cascade. We also observed differential effects of high-glucose and fatty acid treatment on glucose uptake and long-chain fatty acyl-CoA profiles, and in particular an accumulation of palmitoleoyl-CoA in cells overexpressing SCD1. Conclusions/interpretation Insulin-resistant skeletal muscle of ZDF rats is characterised by a specific gene expression profile with increased levels of Scd1. An insulin-resistant phenotype similar to that obtained by treatment with palmitate and high glucose can be induced in vitro by overexpression of SCD1 in muscle cells. This supports the hypothesis that elevated SCD1 expression is a possible cause of insulin resistance and type 2 diabetes.