Differential effects of rexinoids and thiazolidinediones on metabolic gene expression in diabetic rodents.
Both retinoid X receptor (RXR)-selective agonists (rexinoids) and thiazolidinediones (TZDs), PPAR (peroxisome proliferator-activated receptor)-gamma-specific ligands, produce insulin sensitization in diabetic rodents. In vitro studies have demonstrated that TZDs mediate their effects via the RXR/PPAR-gamma complex. To determine whether rexinoids lower hyperglycemia by activating the RXR/PPAR-gamma heterodimer in vivo, we compared the effects of a rexinoid (LG100268) and a TZD (rosiglitazone) on gene expression in white adipose tissue, skeletal muscle, and liver of Zucker diabetic fatty rats (ZDFs). In adipose tissue, rosiglitazone decreased tumor necrosis factor-alpha (TNF-alpha) mRNA and induced glucose transporter 4 (GLUT4), muscle carnitine palmitoyl-transferase (MCPT), stearoyl CoA desaturase (SCD1), and fatty acid translocase (CD36). In contrast, LG100268 increased TNF-alpha and had no effect or suppressed the expression of GLUT4, MCPT, SCD1, and CD36. In liver, the rexinoid increased MCPT, SCD1, and CD36 mRNAs, whereas rosiglitazone induced only a small increase in CD36. In skeletal muscle, rosiglitazone and LG100268 have similar effects; both increased SCD1 and CD36 mRNAs. The differences in the pattern of genes induced by the rexinoids and the TZDs in diabetic animals found in these studies suggests that these compounds may have independent and tissue-specific effects on metabolic control in vivo.
Singh Ahuja
H
H
Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, Texas 77030, USA.
Liu
S
S
Crombie
D L
DL
Boehm
M
M
Leibowitz
M D
MD
Heyman
R A
RA
Depre
C
C
Nagy
L
L
Tontonoz
P
P
Davies
P J
PJ
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D006946:Hyperinsulinism / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009539:Nicotinic Acids / Q000494:pharmacology*; D009765:Obesity; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors; D000077154:Rosiglitazone; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D009539:Nicotinic Acids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; C095104:LG 100268