Reduction of intramyocellular lipid following short-term rosiglitazone treatment in Zucker fatty rats: an in vivo nuclear magnetic resonance study.
The aim of the study was to characterize the effects of rosiglitazone, an oral insulin sensitizer, on intramyocellular lipid (IMCL) content in tibialis anterior muscle and whole body lipid deposition in Zucker fatty rats using in vivo (1)H nuclear magnetic resonance (NMR) spectroscopy. The IMCL/EMCL (extramyocellular) ratio was significantly lower in the rosiglitazone (FRSG) group at 7, 14, 21, and 28 days of treatment at 3 mg/kg/d (0.04 +/- 0.01, 0.09 +/- 0.03, 0.11 +/- 0.02, and 0.07 +/- 0.02, respectively) versus baseline (0.43 +/- 0.12, P <.01 v all time points), whereas there was no difference in the control (FC) group at these time points (0.31 +/- 0.08, 0.36 +/- 0.08, 0.40 +/- 0.14, and 0.49 +/- 0.18, respectively) versus baseline (0.37 +/- 0.07). Absolute IMCL content was also lower at 28 days in the FRSG (0.41 +/- 0.09 micromol/g) versus FC (2.13 +/- 0.40 micromol/g, P <.005) group. To further characterize the temporal nature of this change, the IMCL/EMCL ratio was examined in the FRSG group on each of the first 4 days of treatment, and a steady decline was observed (0.38 +/- 0.12, 0.21 +/- 0.08, 0.12 +/- 0.04, 0.09 +/- 0.04, 0.05 +/- 0.03 at baseline and days 1, 2, 3, and 4 respectively, P <.05 baseline v all time points). To examine the relationship between IMCL and insulin sensitivity, a euglycemic-hyperinsulinemic clamp and IMCL measurement was performed on 7-day treated FRSG and FC groups. There was a negative correlation between absolute IMCL content and glucose infusion rate (r = -0.47, P <.04). The FRSG and the FC groups had similar whole body lipid content (expressed as a percentage of whole body water content) at baseline (48% +/- 5% and 44% +/- 2%, respectively), but the value was greater in the FRSG group following 28 days of treatment (103% +/- 4 v 84% +/- 6%, respectively, P <.02). In summary, there was a rapid (days) and pronounced reduction ( downward arrow approximately 70%) in IMCL content in tibialis anterior muscle following rosiglitazone treatment. Additionally, the increase in whole body lipid in the FRSG group suggests that there was increased adipocyte lipid storage following long-term rosiglitazone treatment. These results support the hypothesis that rosiglitazone indirectly increases peripheral insulin sensitivity by decreasing adipocyte lipolysis, thereby lowering IMCL content.
Jucker
Beat M
BM
Department of Cardiovascular and Urogenital Investigational Biology and Product Support, Laboratory of Animal Sciences, Clinical Development, and Technology Development, GlaxoSmithKline, King of Prussia, PA 19406, USA.
Schaeffer
Thomas R
TR
Haimbach
Robin E
RE
Mayer
Matthew E
ME
Ohlstein
Derek H
DH
Smith
Stephen A
SA
Cobitz
Alexander R
AR
Sarkar
Susanta K
SK
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism; D008055:Lipids / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology; D009765:Obesity / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain
D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone