Treatment of obesity-related inflammation with a novel synthetic pentacyclic oleanane triterpenoids via modulation of macrophage polarizationResearch in context

Background: Obesity leads to the chronic inflammation in the whole body and triggers the macrophage polarization to the pro-inflammatory phenotype. Targeting macrophage polarization provides a promising therapeutic strategy for obesity-related metabolic disorders and inflammation. Here, we show that SO1989, a derivative of natural occurring compound oleanolic acid, restores the balance between M1-polarized and M2-polarized macrophages in high fat diets (HFD)-induced obese mice resulting in the improvement of adipose inflammation and the metabolic dysfunctions. Methods: Histological analysis, magnetic cell sorting and FACS, in vitro cell model of adipose inflammation, Western blotting, HFD mice model. Findings: SO1989 exhibits similar or even stronger activity in inhibiting inflammation and M1 polarization of macrophages both in vitro and in vivo compared to its analogue CDDO-Me, previously known as a powerful anti-inflammation chemical small molecule. In addition, SO1989 can significantly increase the level of fatty acid oxidation in macrophages which can efficiently facilitate M2 polarization of macrophages. Unlike CDDO-Me, SO1989 shows less adverse effects on obese mice. Interpretation: Taken all together, our findings identify SO1989 as a modulator in macrophage polarization and a safer potential leading compound for pro-resolution of inflammation treatment in metabolic disorders. Fund: Supported by grants from the National Key Research and Development Plan (2017YFA0506000, 2017YFA0205400) and National Natural Science Foundation of China (81673439) and Natural Science Fund project in Jiangsu Province (BK20161408). Keywords: Inflammation, Macrophage polarization, SO1989, Fatty acid oxidation, Adverse effects