Abstract
The chronic low-grade inflammation of adipose tissues, primarily mediated by adipose tissue macrophages (ATMs), is the key pathogenic link between obesity and metabolic disorders. Oleanolic acid (OA) is a natural triterpenoid possessing anti-diabetic and anti-inflammation effects, but the machinery is poorly understood. This study investigated the detailed mechanisms of OA on adipose tissue inflammation in obese mice. C57BL/6J mice were fed with high-fat diet (HFD) for 12 weeks, then daily intragastric administrated with vehicle, 25 and 50 mg/kg OA for 4 weeks. Comparing with vehicle, OA administration in obese mice greatly improved insulin resistance, and reduced adipose tissue hypertrophy, ATM infiltration as well as the M1/M2 ratio. The pro-inflammatory markers were significantly down-regulated by OA in both adipose tissue of obese mice and RAW264.7 macrophages treated with interferon gamma/lipopolysaccharide (IFN-γ/LPS). Furthermore, it was found that OA suppressed activation of mitogen-activated protein kinase (MAPK) signaling and NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome through decreasing voltage dependent anion channels (VDAC) expression and reactive oxygen species (ROS) production. This is the first report that oleanolic acid exerts its benefits by affecting mitochondrial function and macrophage activation.
Highlights
In recent years, obesity has become a seriously global threat to human health, which lowers the quality of people’s life
C57BL/6J mice were fed with high-fat diet (HFD) for 12 weeks, and the mice body weight increased significantly, the impaired glucose tolerance suggested establishment of the obesity model, compared with the mice fed with normal diet (ND) (Supplementary Figure 2)
The improvement in inflammation, glucose tolerance, and insulin sensitivity in the Oleanolic acid (OA)-treated mice sustained in the bodyweight matched groups (Supplementary Figure 3)
Summary
Obesity has become a seriously global threat to human health, which lowers the quality of people’s life. It has been found that obesity-induced inflammation begins with white adipose tissue (WAT), accompanied with the steady development to IR, and eventually the inflammation become systemic (Xu et al, 2003). Especially macrophages, are key players in this development of inflammation in obese individuals (Shoelson et al, 2007). The up-regulation of macrophage-related genes is mainly induced in WAT (Xu et al, 2003). The adipose tissue macrophage (ATM) is essential in the pathogenesis of obesity and related metabolic disorders, both in genetic and diet-induced overweight rodents and obese patients (Weisberg et al, 2003)
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