Differential effects of rosiglitazone on skeletal muscle and liver insulin resistance in A-ZIP/F-1 fatless mice.
To determine the role of adipocytes and the tissue-specific nature in the insulin sensitizing action of rosiglitazone, we examined the effects of 3 weeks of rosiglitazone treatment on insulin signaling and action during hyperinsulinemic-euglycemic clamps in awake A-ZIP/F-1 (fatless), fat-transplanted fatless, and wild-type littermate mice. We found that 53 and 66% decreases in insulin-stimulated glucose uptake and insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity in skeletal muscle of fatless mice were normalized after rosiglitazone treatment. These effects of rosiglitazone treatment were associated with 50% decreases in triglyceride and fatty acyl-CoA contents in the skeletal muscle of rosiglitazone-treated fatless mice. In contrast, rosiglitazone treatment exacerbated hepatic insulin resistance in the fatless mice and did not affect already reduced IRS-2-associated PI 3-kinase activity in liver. The worsening of insulin action in liver was associated with 30% increases in triglyceride and fatty acyl-CoA contents in the liver of rosiglitazone-treated fatless mice. In conclusion, these data support the hypothesis that rosiglitazone treatment enhanced insulin action in skeletal muscle mostly by its ability to repartition fat away from skeletal muscle.
Kim
Jason K
JK
Department of Internal Medicine, Section of Endocrinology, Howard Hughes Medical Institute, Yale University School of Medicine, S269C CAB, PO Box 208020, New Haven, CT 06520-8020, USA. jason.k.kim@yale.edu
Fillmore
Jonathan J
JJ
Gavrilova
Oksana
O
Chao
Lily
L
Higashimori
Takamasa
T
Choi
Hyejeong
H
Kim
Hyo-Jeong
HJ
Yu
Chunli
C
Chen
Yan
Y
Qu
Xianqin
X
Haluzik
Martin
M
Reitman
Marc L
ML
Shulman
Gerald I
GI
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D005260:Female; D015309:Glucose Clamp Technique; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone