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This version published online on September 16, 2004
Endocrinology, doi:10.1210/en.2004-0659
A more recent version of this article appeared on December 1, 2004
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Submitted on May 24, 2004
Accepted on September 7, 2004

Rosiglitazone Enhances Glucose Tolerance by Mechanisms Other Than Reduction of Fatty Acid Accumulation Within Skeletal Muscle

Sarah J. Lessard, Sonia L. Lo Giudice, Winnie Lau, Julianne J. Reid, Nigel Turner, Mark A. Febbraio, John A. Hawley, and Matthew J. Watt*

Exercise Metabolism Group, Skeletal Muscle Research Laboratory and Diabetic Complications Group, School of Medical Sciences, RMIT University, Bundoora, Victoria 3083, Metabolic Research Centre and Department of Biomedical Science, University of Wollongong, Wollongong, NSW 2522

* To whom correspondence should be addressed. E-mail: matthew.watt{at}rmit.edu.au.

We hypothesized that improved glucose tolerance with rosiglitazone treatment would coincide with decreased levels of intramuscular triacylglycerol (IMTG), diacylglycerol and ceramide. Obese Zucker rats were randomly divided into two experimental groups: control (OB CON, n = 9) and rosiglitazone (OB RSG, n = 9), with lean Zucker rats (LN CON, n = 9) acting as a control group for obese control. Rats received either vehicle, or 3 mg/kg rosiglitazone for 6 wk. Glucose tolerance was impaired (P < 0.01) in obese compared with lean rats, but was normalized following rosiglitazone treatment. IMTG content was higher in obese compared with lean rats (70.5 ± 5.1 vs. 27.5 ± 2.0 µmol.g-1 dm, P < 0.05), and increased a further 30% (P < 0.05) with rosiglitazone treatment. Intramuscular fatty acid composition shifted toward a higher proportion of monounsaturates (P < 0.05) in obese rosiglitazone treated rats, due to an increase in palmitoleate (16:1, P < 0.05). Rosiglitazone treatment increased (P < 0.05) skeletal muscle diacylglycerol and ceramide levels by 65% and 100%, respectively, compared with obese rats, but elevated muscle diacylglycerol was not associated with changes in the total or membrane content of the diacylglycerol-sensitive PKC isoforms {theta}, {delta}, {alpha} and {beta}. In summary, we observed a disassociation between skeletal muscle IMTG, diacylglycerol and ceramide content and glucose tolerance with rosiglitazone treatment in Obese Zucker rats. Our data suggest, therefore, that rosiglitazone enhances glucose tolerance by mechanisms other than reduction of fatty acid accumulation within skeletal muscle.
Key words: Obesity • IMTG • ceramide • diacylglycerol • hormone sensitive lipase




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