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

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).