Protection of Adipose Tissue by Pioglitazone in a Mouse Model of Doxorubicin Treatment

Cancer is a global epidemic with increasing incidence, which needs continuous efforts to enhance treatment efficacy and reduce side effects. Our study focuses on the impact of doxorubicin, a widely used chemotherapeutic agent, on white adipose tissue (WAT) homeostasis and explores the potential mitigating effects of coadministration with pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPARγ) activator. Using male C57BL/6 mice, we investigated the influence of doxorubicin and pioglitazone on WAT, considering factors such as weight loss, metabolic parameters, lipolysis, adipokines, and immune cell infiltration. Doxorubicin treatment resulted in weight loss, specifically affecting visceral adipose tissue, while coadministration with pioglitazone preserved inguinal adipose tissue (iWAT). Metabolic analyses revealed that doxorubicin induced hypoglycaemia, mitigated by pioglitazone, without significant effects on lipid profiles. Pioglitazone ameliorated the doxorubicin-induced reduction in adiponectin, thereby contributing to the maintenance of glucose homeostasis. Lipolysis assays demonstrated doxorubicin-induced lipotoxicity, particularly in (iWAT), which was attenuated by pioglitazone. Histological analysis showed no significant changes in adipocyte size, while flow cytometry revealed a reduction in pro-inflammatory M1 macrophages in the co-treated group. Based on gene expression profiles, pioglitazone appeared to modulate genes involved in lipid metabolism, with preliminary indications of a potential role in adipogenic processes. In summary, coadministration of pioglitazone during doxorubicin treatment appeared to attenuate alterations in WAT homeostasis associated with lipotoxicity. These findings contribute to the understanding of potential supportive strategies during doxorubicin-based chemotherapy. Further studies should be conducted to define appropriate dosing regimens, treatment durations, and to evaluate potential effects on cancer progression and patient outcomes.