In vivo effects of pioglitazone on uncoupling protein-2 and -3 mRNA levels in skeletal muscle of hyperglycemic KK mice.
Pioglitazone is a thiazolidinedione drug (TZD) which potently and specifically stimulates peroxisome proliferator-activated receptor gamma (PPAR gamma) and sensitizes cells to insulin. Since TZDs are thought to increase energy expenditure, changes in mitochondrial thermogenesis uncoupling protein-2 and -3 mRNA levels in response to pioglitazone treatment were measured in mouse skeletal muscle. Normally hyperglycemic and hyperinsulinemic KK/Ta mice were given pioglitazone for 2 weeks to treat this non-insulin dependent diabetes-like condition. During treatment, UCP2 mRNA levels increased to 185% of normal untreated control levels in soleus muscle. In contrast, UCP3 mRNA levels significantly decreased, up to 67% of normal untreated control levels. Interestingly, UCP3 mRNA levels correlated quite strongly with blood glucose levels, with r = 0.82 for gastrocnemius tissue and r = 0.92 for soleus tissue. These results may indicate that pioglitazone increases glucose catabolism by direct upregulation of muscle UCP2 gene expression in vivo. Therefore, UCP3 gene expression is controlled by a different mechanism than UCP2 expression.
Shimokawa
T
T
Molecular Medicine Laboratories, Institute for Drug Discovery Research, Tsukuba, Japan. simokawa@yamanouchi.co.jp
Kato
M
M
Watanabe
Y
Y
Hirayama
R
R
Kurosaki
E
E
Shikama
H
H
Hashimoto
S
S
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007279:Injections, Subcutaneous; D007473:Ion Channels; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D000077205:Pioglitazone; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage*; D045162:Thiazolidinediones; D014475:Uncoupling Agents / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D012333:RNA, Messenger; D013844:Thiazoles; D045162:Thiazolidinediones; C000604390:Ucp2 protein, mouse; C000604393:Ucp3 protein, mouse; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D000077205:Pioglitazone