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

Significance Statement

Metaflammation is known as chronic low-grade metabolic inflammation in adipose tissue that drives obesity-induced insulin resistance. Clinical studies using non-steroid anti-inflammatory drugs (NSAIDs) such as salicylates have established a causative role of metaflammation in the pathogenesis of metabolic diseases and associated complications.

As a proof-of concept study, Chen et al. demonstrated the effectiveness of a newly identified benzenediamine derivative (FC98, PubChem CID: 14989837) against obesity-induced insulin resistance by reducing the degree of metaflammation and adipose tissue macrophage (ATM) infiltration using a high fat diet induced obesity (DIO) mouse model.

This work highlighted the potential of novel benzenediamine derivatives against obesity-induced insulin resistance and also provided evidence for targeting metaflammation as a therapeutic strategy for metabolic diseases.

About the author

Changmai Chen: A graduate student at the College of Life Sciences of Nanjing University and State Key Laboratory of Pharmaceutical Biotechnology. His research interest includes molecular pharmacology, endocrine pharmacology and translational pharmacology with focus on lead compound identification and mechanism studies. His mentors are Drs. R.X. Tan and E. Li.

Journal Reference

Eur J Pharmacol. 2015;761:298-308.

Chen C¹, Zhang W², Shi H², Zhuo Y³, Yang G⁴, Zhang A⁵, Hou Y², Xiang Tan R⁵, Li E⁶.

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Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China; Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, China; College of Life Sciences, Nanjing University, China.
Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China; Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, China.
Nanjing Children’s Hospital, Nanjing Medical University, China.
Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, China; Nanjing Children’s Hospital, Nanjing Medical University, China.
Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China; College of Life Sciences, Nanjing University, China.
Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China; Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, China. Electronic address: [email protected].

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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-1β release with ELISA. The in vivo activity was assayed in C57BL/6Jmice 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. FC98exhibited anti-inflammatory activity against LPS- and FFAs-induced IL-1β, 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-1β 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.

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