Impact of Doxorubicin Treatment on the Physiological Functions of White Adipose Tissue

Abstract

White adipose tissue (WAT) plays a fundamental role in maintaining energy balance and important endocrine functions. The loss of WAT modifies adipokine secretion and disrupts homeostasis, potentially leading to severe metabolic effects and a reduced quality of life. Doxorubicin is a chemotherapeutic agent used clinically because of its good effectiveness against various types of cancer. However, doxorubicin has deleterious effects in many healthy tissues, including WAT, liver, and skeletal and cardiac muscles. Our objective was to investigate the effects of doxorubicin on white adipocytes through in vivo and in vitro experiments. Doxorubicin reduced the uptake of glucose by retroperitoneal adipocytes and 3T3-L1 cells via the inhibition of AMP-activated protein kinase Thr172 phosphorylation and glucose transporter 4 content. Doxorubicin also reduced the serum level of adiponectin and, to a greater extent, the expression of genes encoding lipogenic (Fas and Acc) and adipogenic factors (Pparg, C/ebpa, and Srebp1c) in retroperitoneal adipose tissue. In addition, doxorubicin inhibited both lipogenesis and lipolysis and reduced the hormone-sensitive lipase and adipose tissue triacylglycerol lipase protein levels. Therefore, our results demonstrate the impact of doxorubicin on WAT. These results are important to understand some side effects observed in patients receiving chemotherapy and should encourage new adjuvant treatments that aim to inhibit these side effects.

Adipocytes as Anticancer Drug Delivery Depot

“…pDox@adipocytes showed enhanced cytotoxicity compared with Dox@adipocytes, and this effect was significantly reduced by BMS309403 that inhibits FABP4 (iFABP4) ( Figure 2J). In accordance with a previous report, 26 Dox inhibited lipid accumulation in adipocytes (Figures 2K, S17A, and S17B). In addition, pDox could be efficiently encapsulated into adipocytes ( Figure 2L) and accumulated in the lipid droplets ( Figure 2M).…”

Doxorubicin Induces Inflammatory Modulation and Metabolic Dysregulation in Diabetic Skeletal Muscle

“…Since the phosphorylation of ACC was significantly downregulated in our examined muscles, we suspected that DOX decreased fatty acid oxidative metabolism in diabetic skeletal muscle. It has been reported that oxidative phosphorylation (OXPHOS) genes are strongly correlated to PGC1α in diabetic skeletal muscle based on DNA microarray analysis (Mootha et al, 2003 ); also, it has been reported that DOX treatment in the heart inhibited oxidative phosphorylation (Abdel-aleem et al, 1997 ) and reduced phosphorylation of ACC in white adipose tissue (Biondo et al, 2016 ). Consistently, we demonstrated in our examined muscle, the decreases in AMPK and PGC1α, which induced glycolytic shift as indicated by the downregulation of pACCSer79.…”

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

“…More importantly, doxorubicin treatment causes adipose tissue and/or adipocyte dysfunction, by altering lipogenesis (decreased FAS) and lipolysis (increased HSL) (20-22, 64, 91), which participate toward the disruption of adipose tissue homeostasis. The consequence here is an increase in FFA release that disrupts lipid storage (22). Doxorubicin-induced FFA release may further exacerbate the bioavailability of FFA, which cancer cells can utilize favorably for its survival and proliferation demands, and thereby indirectly promote breast cancer treatment resistance.…”

“…Despite doxorubicin's high efficacy in killing cancer cells, its' clinical efficacy is hindered by the development of various cellular toxicities which contributes to the development of chemotherapeutic drug resistance (20). Doxorubicin treatment is also associated with cellular toxicities in adipose tissue (primary storage site for FAs) which in turn leads to dysfunctional lipid/FA storage (21,22). Therefore, FA tissue composition may also be significantly altered by chemotherapeutic agents.…”