Proliferative and Molecular Effects of the Dual PPARα/γ Agonist Tesaglitazar in Rat Adipose Tissues: Relevance for Induction of Fibrosarcoma

Abstract

The dual peroxisome-proliferator-activated receptor (PPAR) a/g agonist tesaglitazar has been shown to produce fibrosarcomas in rats. Here, the authors studied morphology, proliferation, differentiation, and inflammation markers in adipose tissue from rats exposed to 1, 3, or 10 mmol/kg tesaglitazar for 2 or 12 weeks, including recovery groups (12 weeks treatment followed by 12 weeks recovery), and 3 or 10 mmol/kg tesaglitazar for 24 weeks. Subcutaneous white and brown fat revealed reversible dose-related histopathological alterations and after 12 and 24 weeks developed areas of thickened skin (fatty lumps). There was a dose-dependent increase in proliferation of interstitial cells in white and brown fat as shown by increased mitotic index in all dose groups after 2 weeks. This was limited to the high dose after 12 and 24 weeks in white fat. Gene expression analyses showed that while tesaglitazar induced differentiation of adipose tissue characterized with a switch in cyclin D1 and D3 mRNA by 12 weeks, longer exposure at high doses reversed this differentiation concurrent with a reappearance of early adipocyte and inflammatory markers. These data suggest that sustained increased turnover of mesenchymal cells in adipose tissues, concomitant with onset of inflammation and fibrosis, drives development of fibrosarcomas in rats treated with tesaglitazar.

Conservation of Binding Epitopes for Monoclonal Antibodies on the Rabies Virus Glycoprotein

“…Additionally, Kaletra reduced the ratio of cyclin D1 (CCND1) to cyclin D3 (CCND3) in both inguinal and epididymal fat ( Figure 3B). Since D1 is typically found in proliferating cells while D3 is important for fat cell terminal differentiation and maintenance [25][26][27], a reduction in the D1/D3 ratio suggests that Kaletra promote fat cell differentiation in vivo, which could contribute to explain the marked increase of epididymal fat mass ( Figure 2B). Besides, Kaletra-associated reduction in TNFα expression implies that fat tissue inflammation is unlikely a main contributor to the druginduced loss of in vivo physical and metabolic function.…”

Lopinavir/Ritonavir Impairs Physical Strength in Association with Reduced Igf1 Expression in Skeletal Muscle of Older Mice

“…Additionally, Kaletra reduced the ratio of cyclin D1 (CCND1) to cyclin D3 (CCND3) in both inguinal and epididymal fat ( Figure 3B ). Since D1 is typically found in proliferating cells while D3 is important for fat cell terminal differentiation and maintenance [ 25 – 27 ], a reduction in the D1/D3 ratio suggests that Kaletra promote fat cell differentiation in vivo , which could contribute to explain the marked increase of epididymal fat mass ( Figure 2B ). Besides, Kaletra-associated reduction in TNFα expression implies that fat tissue inflammation is unlikely a main contributor to the drug-induced loss of in vivo physical and metabolic function.…”

Caracterização dos pacientes portadores de sarcoma de aplicação felino quanto ao escore de condição corporal, à origem de sua formação e ao microambiente de seu desenvolvimento

“…O tecido adiposo é capaz de estimular e manter o processo inflamatório (COPPACK, 2001;TRAYHURN;BING, 2006). Em ratos, quando estimulado por meio de agonistas de PPAR induziu-se sarcoma em tecido subcutâneo de parede torácica-abdominal (GLINGHAMMAR, 2011).…”