Comparison of adipose tissue changes following administration of rosiglitazone in the dog and rat.
Rosiglitazone (BRL-49653-C), a thiazolidinedione, is a potent agonist for the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma). Thiazolidinediones have been reported to induce adipocyte differentiation in vitro and there is limited data on their effects in vivo. The objective of this study was to compare the effects of rosiglitazone on adipocyte differentiation between dogs and rats. Morphological (light and ultrastructural) and morphometric evaluations were conducted on perirenal adipose tissue from dogs that have been treated for 1 month with 0.4, 5, 60 mg/kg/day and rats treated for the same period with 80 mg/kg/day. There was a dose-related change in the phenotype of white adipose tissue in dogs, reflected by an increase in nuclear numerical density (up to threefold) and cytoplasmic area fraction (up to 2.1-fold). In addition, there was an enlargement of the nuclei and a reduction in the size of the white adipocyte lipid vacuoles. Ultrastructural changes included an increase in the number of mitochondria per adipocyte. In the rat, similar changes were seen in nuclear numerical density (1.5-fold increase) and cytoplasmic area fraction (2.2-fold increase). There were also increased numbers of mitochondria per cell in white adipocytes giving them similar numbers of mitochondria to brown adipocytes. In the brown adipocytes, there was a reduction in cytoplasmic area fraction with a corresponding increase in the size of the lipid filled vacuoles in other words there was a converging of the phenotypes of the white and brown adipose tissues.
Toseland
C D
CD
Safety Assessment, SmithKline Beecham, Welwyn, Herts, UK. C_Nigel_Toseland@SBPHRD.com
Campbell
S
S
Francis
I
I
Bugelski
P J
PJ
Mehdi
N
N
D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007441:Intubation, Gastrointestinal; D008297:Male; D008854:Microscopy, Electron; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D012737:Sex Factors; D013844:Thiazoles / Q000008:administration & dosage*; D045162:Thiazolidinediones
D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone