A novel benzenediamine derivative FC98 reduces insulin resistance in high fat diet-induced obese mice by suppression of metaflammation.

ABSTRACT

Chronic low-grade metabolic inflammation (metaflammation) is a hallmark of metabolic diseases. 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-1ß 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(+)CD11b(+) macrophage infiltration. FC98 exhibited anti-inflammatory activity against LPS- and FFAs-induced IL-1ß, IL-6, and TNF-α gene expression and JNK and p38 activation. The IC50 for FC98 to inhibit NO production was determined at 6.8µM. FC98 also dose-dependently inhibited IL-1ß secretion. In DIO mice, FC98 at 10 and 20mg/kg significantly improved metabolic parameters, including body weight, fat mass, glucose disposal and insulin sensitivity. The reduction in adipocyte area, F4/80(+)CD11b(+) macrophage infiltration, proinflammatory gene expression, along with JNK activation, was also significant in those groups. 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.