Abstract
Pazopanib is a multikinase inhibitor with anti-tumor activity. As of now, the anti-obesity effect and mode of action of pazopanib are unknown. In this study, we investigated the effects of pazopanib on lipid accumulation, lipolysis, and expression of inflammatory cyclooxygenase (COX)-2 in differentiating and differentiated 3T3-L1 cells, a murine preadipocyte. Of note, pazopanib at 10 µM markedly decreased lipid accumulation and triglyceride (TG) content during 3T3-L1 preadipocyte differentiation with no cytotoxicity. Furthermore, pazopanib inhibited not only expression of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), and perilipin A but also phosphorylation of signal transducer and activator of transcription (STAT)-3 during 3T3-L1 preadipocyte differentiation. In addition, pazopanib treatment increased phosphorylation of cAMP-activated protein kinase (AMPK) and its downstream effector ACC during 3T3-L1 preadipocyte differentiation. However, in differentiated 3T3-L1 adipocytes, pazopanib treatment did not stimulate glycerol release and hormone-sensitive lipase (HSL) phosphorylation, hallmarks of lipolysis. Moreover, pazopanib could inhibit tumor necrosis factor (TNF)-α-induced expression of COX-2 in both 3T3-L1 preadipocytes and differentiated cells. In summary, this is the first report that pazopanib has strong anti-adipogenic and anti-inflammatory effects in 3T3-L1 cells, which are mediated through regulation of the expression and phosphorylation of C/EBP-α, PPAR-γ, STAT-3, ACC, perilipin A, AMPK, and COX-2.
Highlights
Obesity is defined as abnormal fat accumulation in the human body
In the absence of pazopanib, there was a high accumulation of lipid droplets (LDs) in 3T3-L1 cells on D8 of differentiation compared with undifferentiated cells at D0 (Figure 1B, upper panels)
We report that pazopanib at 10 μM has anti-adipogenic and anti-inflammatory, but not lipolytic, effects on 3T3-L1 cells, and these effects are mediated through control of the expression and phosphorylation levels of
Summary
Obesity is defined as abnormal fat accumulation in the human body. Obesity has become a global pandemic, based on the fact that it is highly associated with the development of many human chronic diseases such as type 2 diabetes, hypertension, and cancer [1,2]. Adipocytes in the adipose tissues (ATs) can be exposed to various types of internal and external stimuli, such as pro-inflammatory cytokines, free fatty acids, or lipopolysaccharide (LPS), and they are thought to express and secrete many inflammatory factors, leading to the development of obesity inflammation [20,21,22]. Inhibition (or an inhibitor) of TNF-α-induced COX-2 expression in (pre)adipocytes is considered as a potential target in alleviating obesity inflammation. We investigated the regulatory effects of pazopanib on lipid accumulation, lipolysis, and expression of TNF-α-induced COX-2 in 3T3-L1 cells. We here demonstrate that pazopanib has strong anti-adipogenic and antiinflammatory, but not lipolytic, effects on 3T3-L1 cells, which are mediated through control of the expression and phosphorylation of C/EBP-α, PPAR-γ, STAT-3, ACC, perilipin A, AMPK, and COX-2
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
