FC98 Reduces Obesity-induced Insulin Resistance By Suppression Of Metaflammation

Obesity-associated metabolic syndrome is now considered as a pathological characteristic most closely associated with metabolic chronic low-grade inflammation (metaflammation). Metaflammation in adipose tissue can drive development of obesity-induced insulin resistance, which is involved in the overexpression of proinflammatory cytokines and the infiltration of the adipose tissue macrophages (ATMs). The ATMs content correlates positively with two indices of adiposity:BMI and adipocyte size. Macrophages surrounding dying or dead adipocytes form crown-like structures (CLSS), which is significantly related to the process of obesity-associated diseases. Targeting metaflammation has emerged as one of the most important research hot spots in the study of obesity-induced insulin resistance.The aim of this study was to determine the effectiveness of a newly identified benzenediamine derivative (FC98, PubChem CID:14989837) against metaflammation and insulin resistance using a high fat diet-induced obesity (DIO) murine model. LPS and free fatty acids (FFAs)-induced gene expression and signaling was determined in cell culture systems. Inflammasome activation was determined by measuring IL-1β release with ELISA. The in vivo activity was assayed in C57BL/6J mice fed with a high fat diet (HFD) by measuring body weight gains, glucose tolerance and insulin sensitivity. The effect was also evaluated by H&E and IHC staining, by measuring gene expression and cytokine production, and by analysis of F4/80+CDllb+macrophage infiltration.FC98 exhibited anti-inflammatory activity against LPS- and FFAs-induced IL-1β, IL-6, and TNF-a gene expression and JNK and p38 activation. The IC50 for FC98 to inhibit NO production was determined at 6.8 μM. FC98 also dose-dependently inhibited IL-1] secretion. In DIO mice, FC98 at 10 and 20 mg/kg significantly improved metabolic parameters, including body weight, fat mass, glucose disposal and insulin sensitivity. The reduction in adipocyte area, F4/80+CDllb+ macrophage infiltration, proinflammatory gene expression, along with JNK activation, was also significant in those groups. The percentage of F4/80+CD11b+ macrophages in ND group was detected at 25.6%, while those in vehicle-treated group were detected at 54.1%. FC98 treatment notably reduced F4/80 and CD11b positive macrophages (F4/80+CD11b+), detected at 41.7%(10 mg/kg group) and 32.5%(20 mg/kg group). Those results demonstrated that FC98 suppressed proinflammatory macrophage infiltration. Additionally, FC98-treated animals had increased AKT phosphorylation in response to insulin stimulation. FC98 inhibits metaflammation and ameliorates insulin resistance mainly by inhibiting signaling pathways of proinflammatory response in DIO animals. This study highlights the significance of targeting metaflammation for obesity-attributive metabolic syndrome.In conclusion, this study highlights the significance of targeting metaflammation for obesity-induced insulin resistance. Here, we not only identified small molecular compounds that contribute to suppressing metaflammation in obese mice but also a strategy for treating obesity-mediated insulin resistance.