The Dietary Isoflavone Daidzein Reduces Expression of Pro-Inflammatory Genes through PPARα/γ and JNK Pathways in Adipocyte and Macrophage Co-Cultures

Abstract

Obesity-induced inflammation caused by adipocyte-macrophage interactions plays a critical role in developing insulin resistance, and peroxisome proliferator-activated receptors (PPARs) regulate inflammatory gene expression in these cells. Recently, the soy isoflavone daidzein was reported to act as a PPAR activator. We examined whether daidzein affected adipocyte-macrophage crosstalk via the regulation of PPARs. Co-cultures of 3T3-L1 adipocytes and RAW264 macrophages, or palmitate-stimulated RAW264 macrophages were treated with daidzein in the presence or absence of specific inhibitors for PPARs: GW6471 (a PPARα antagonist), and GW9662 (a PPARγ antagonist). Inflammatory gene expression was then determined. Daidzein significantly decreased chemokine (C-C motif) ligand 2 (Ccl2, known in humans as monocyte chemo-attractant protein 1 (MCP1)) and interleukin 6 (Il6) mRNA levels induced by co-culture. In 3T3-L1 adipocytes, daidzein inversed the attenuation of adiponectin gene expression by co-culture, and these effects were inhibited by the PPAR-γ specific inhibitor. Daidzein also decreased Ccl2 and Il6 mRNA levels in RAW264 macrophages stimulated with palmitate or conditioned medium (CM) from hypertrophied 3T3-L1 adipocytes. This inhibitory effect on Il6 expression was abrogated by a PPAR-α inhibitor. Additionally, we examined the activation of nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways and found that daidzein significantly inhibited palmitate-induced phosphorylation of JNK. Our data suggest that daidzein regulates pro-inflammatory gene expression by activating PPAR-α and -γ and inhibiting the JNK pathway in adipocyte and macrophage co-cultures. These effects might be favorable in improving adipose inflammation, thus, treatment of daidzein may be a therapeutic strategy for chronic inflammation in obese adipose tissue.

Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae

“…L-FABP has been shown to regulate PPAR-␣ transcriptional activity in hepatocytes through direct protein-protein interactions with PPAR-␣ (43). PPAR-␣ exerts it is anti-inflammatory effects through downregulating the secretion of proinflammatory factors (such as TNF-␣) and is also known to inhibit apoptosis via the NF-B signaling pathway (44)(45)(46). Previous studies reported that PPAR-␣ agonists showed both anti-inflammatory and antiapoptotic effects (47,48).…”

Daidzein, its effects on impaired glucose and lipid metabolism and vascular inflammation associated with type 2 diabetes

“…Additionally, the authors reported that in high fat diet‐fed mice daidzein administration also upregulated the gene expression of PPARγ and adiponectin and downregulated the MCP‐1 and TNFα gene expression in fat tissue and thereby inhibited hypertrophy in fat cell size and improved insulin sensitivity . In another study, Sakamoto et al further reported the role of PPAR and JNK pathways in mediating the anti‐inflammatory effect of daidzein. Results showed that daidzein treatment caused a significant increase in PPARα transcriptional activity and a decrease in JNK phosphorylation followed by down‐regulation in the mRNA expression of Ccl2 and IL6 in palmitate‐treated macrophage cells.…”

“…An increase in vascular inflammation plays a critical role in developing insulin resistance. Sakamato et al examined the effect of daidzein on the markers of pro‐inflammatory cytokines in the co‐cultures of 3T3L1 adipocyte and RAW264 macrophage. Results showed that that daidzein (25 μM) treatment significantly inhibited the mRNA expression of pro‐inflammatory cytokines, CCL2 and IL6 in adipocytes induced by co‐culture.…”

“…Many studies have reported the enhanced expression of several pro‐inflammatory cytokines including TNF‐α, IL‐1, IL‐6, and monocytec chemoattractant protein‐1 (MCP‐1) in the context of insulin resistance, obesity, T2Ds, and cardiovascular diseases . Daidzein treatment has been shown to suppress the activation of several inflammatory mediators associated with above‐mentioned diseases . Using adipocyte cell culture model, Sakamoto et al .…”

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“…Sakamoto et al, 65 , suggest that daidzein regulates pro-inflammatory gene expression by activating PPAR-α and -γ and inhibiting the JNK pathway in adipocyte and macrophage co-cultures. Accordingly this study revealed that the levels of daidzein were enhanced in transformed leaves of soybean with RnPPARγ.…”