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 increasin g cell sensitivity to available insulin. Previous studies have shown that r odents treated with high doses of troglitazone develop increased heart weig ht and increased interscapular brown fat. This study investigated cellular proliferation in heart and brown fat of troglitazone-treated mice as well a s possible interactions with an angiotensin-converting enzyme inhibitor (qu inipril). B6C3F(1) female mice were treated daily with either vehicle contr ol, 125 mg/kg quinipril, 1,200 mg/kg troglitazone, or troglitazone/quinipri l combination per os for up to 14 days. Four days before necropsy, mice wer e dosed with bromodeoxyuridine (BrdU) using osmotic pumps. Cell proliferati on in heart, brown fat, and retroperitoneal white fat was investigated by m eans of light microscopic anti-BrdU immunolabeling techniques. Immunoelectr on microscopy was used to determine the cell phenotypes and cellular distri bution of BrdU label in heart and brown fat. Treatment with troglitazone fo r 2 wk resulted in increased heart and brown fat weights but in decreased w hite fat weight. Combination treatment with troglitazone and quinipril also resulted in decreased white fat weight compared with controls. Histologica lly, brown fat adipocytes in troglitazone- and troglitazone/quinipril-treat ed mice had coalescent lipid vacuoles and increased eosinophilia of the cyt oplasm. White fat adipocytes in troglitazone- and troglitazone/quinipril-tr eated 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 quini pril- or troglitazone/quinipril-treated animals. Brown fat BrdU labeling af ter 1 wk was increased in troglitazone- and troglitazone/quinipril-treated mice. Ultrastructural anti-BrdU immunogold labeling demonstrated that trogl itazone-treated heart and brown fat had greater populations of BrdU-labeled cells that were identified as endothelial cells. These results demonstrate d that troglitazone-induced increased cardiac weight in mice can be prevent ed by quinipril and that increased cardiac weight coincides with early incr eased endothelial cell proliferation.