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


METHODS
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
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.
Voss
M D
MD
Sanofi-Aventis Deutschland GmbH, Science and Medical Affairs, TD Metabolism, Industriepark Hoechst, 65926 Frankfurt am Main, Germany. MarcDietrich.Voss@sanofi-aventis.com
Beha
A
A
Tennagels
N
N
Tschank
G
G
Herling
A W
AW
Quint
M
M
Gerl
M
M
Metz-Weidmann
C
C
Haun
G
G
Korn
M
M
D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D018955:CD36 Antigens / Q000032:analysis / Q000235:genetics / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010168:Palmitates / Q000494:pharmacology; D010171:Palmitoyl Coenzyme A / Q000032:analysis / Q000235:genetics / Q000502:physiology; D051381:Rats; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000235:genetics* / Q000378:metabolism*
D000214:Acyl Coenzyme A; D018955:CD36 Antigens; D007328:Insulin; D010168:Palmitates; D010171:Palmitoyl Coenzyme A; D013230:Stearoyl-CoA Desaturase; D005947:Glucose