Troglitazone-induced heart and adipose tissue cell proliferation in mice.
Troglitazone, a thiazolidinedione, is a novel agent for the oral treatment of non-insulin-dependent (Type II) diabetes mellitus; it works by increasing cell sensitivity to available insulin. Previous studies have shown that rodents treated with high doses of troglitazone develop increased heart weight and increased interscapular brown fat. This study investigated cellular proliferation in heart and brown fat of troglitazone-treated mice as well as possible interactions with an angiotensin-converting enzyme inhibitor (quinipril). B6C3F1 female mice were treated daily with either vehicle control, 125 mg/kg quinipril, 1,200 mg/kg troglitazone, or troglitazone/quinipril combination per os for up to 14 days. Four days before necropsy, mice were dosed with bromodeoxyuridine (BrdU) using osmotic pumps. Cell proliferation in heart, brown fat, and retroperitoneal white fat was investigated by means of light microscopic anti-BrdU immunolabeling techniques. Immunoelectron microscopy was used to determine the cell phenotypes and cellular distribution of BrdU label in heart and brown fat. Treatment with troglitazone for 2 wk resulted in increased heart and brown fat weights but in decreased white fat weight. Combination treatment with troglitazone and quinipril also resulted in decreased white fat weight compared with controls. Histologically, brown fat adipocytes in troglitazone- and troglitazone/quinipril-treated mice had coalescent lipid vacuoles and increased eosinophilia of the cytoplasm. White fat adipocytes in troglitazone- and troglitazone/quinipril-treated mice had decreased cell size and increased cytoplasmic eosinophilia. BrdU labeling revealed increased cell proliferation in troglitazone-treated hearts after 1 wk but did not reveal increased cell proliferation in quinipril- or troglitazone/quinipril-treated animals. Brown fat BrdU labeling after 1 wk was increased in troglitazone- and troglitazone/quinipril-treated mice. Ultrastructural anti-BrdU immunogold labeling demonstrated that troglitazone-treated heart and brown fat had greater populations of BrdU-labeled cells that were identified as endothelial cells. These results demonstrated that troglitazone-induced increased cardiac weight in mice can be prevented by quinipril and that increased cardiac weight coincides with early increased endothelial cell proliferation.
Breider
M A
MA
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Co., Ann Arbor, Michigan 48105, USA. Michael.Breider@wl.com
Gough
A W
AW
Haskins
J R
JR
Sobocinski
G
G
de la Iglesia
F A
FA
D017667:Adipocytes / Q000737:chemistry / Q000473:pathology / Q000648:ultrastructure; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000032:analysis / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D016253:Microscopy, Immunoelectron; D009206:Myocardium / Q000166:cytology / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects; D000077583:Quinapril; D044005:Tetrahydroisoquinolines; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D000806:Angiotensin-Converting Enzyme Inhibitors; D002839:Chromans; D007004:Hypoglycemic Agents; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D013844:Thiazoles; D045162:Thiazolidinediones; D001973:Bromodeoxyuridine; D000077288:Troglitazone; D000077583:Quinapril