Phenylmethimazole blocks palmitate-mediated induction of inflammatory cytokine pathways in 3T3L1 adipocytes and RAW 264.7 macrophages

Abstract

Visceral adipocytes and associated macrophages produce and release excessive amounts of biologically active inflammatory cytokines via the portal and systemic vascular system, which induce insulin resistance in insulin target tissues such as fat, liver, and muscle. Free fatty acids (FFAs) absorbed via the portal system or released from adipocytes also induce insulin resistance. In this report, we show that phenylmethimazole (C10) blocks basal IL6 and leptin production as well as basal Socs-3 expression in fully differentiated 3T3L1 cells (3T3L1 adipocytes) without affecting insulin-stimulated AKT signaling. In addition, C10 inhibits palmitate-induced IL6 and iNos up-regulation in both 3T3L1 adipocytes and RAW 264.7 macrophages, LPS-induced NF-kB and IFN-b activation in 3T3L1 cells, and LPS-induced iNos, Ifn-b, Il1b, Cxcl10, and Il6 expression in RAW 264.7 macrophages. C10 also blocks palmitate-induced Socs-3 up-regulation and insulin receptor substrate-1 (IRS-1) serine 307 phosphorylation in 3T3L1 adipocytes. Additionally, we show for the first time that although palmitate increases IRS-1 serine 307 phosphorylation in 3T3L1 adipocytes, AKT serine 473 phosphorylation is enhanced, not reduced, by palmitate. These results suggest that through inhibition of FFA-mediated signaling in adipocytes and associated macrophages, as well as possibly other insulin target cells/tissues (i.e. non-immune cells), C10 might be efficacious to prevent or reverse cytokine-induced insulin resistance seen in obesity-related insulin resistance and type 2 diabetes mellitus.

10E,12Z-conjugated linoleic acid impairs adipocyte triglyceride storage by enhancing fatty acid oxidation, lipolysis, and mitochondrial reactive oxygen species

“…As shown in Fig. 5B , ( 39 ), and monocyte chemotactic factors, such as serum amyloid A-3 (SAA3) and monocyte chemotactic protein-1 (MCP-1) ( 27 ). However, LA (18:2), the all-cis isomer of CLA and a polyunsaturated fatty acid, does not exert proinfl ammatory or chemotactic effects on adipocytes ( 27 ).…”

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“…Our group has identified phenylmethimazole (C10), an inhibitor of pathologic TLR3 signaling/expression, and shown that C10, by virtue of inhibiting the TLR3/Wnt5a pathway is significantly efficacious in in-vitro and in-vivo models of different cancers and auto-immune diseases [1,2,32,33]. Accordingly, in this study, we sought to further investigate the effects of C10 on human breast Figure 4: Combination of tamoxifen and C10 significantly inhibits MCF-7 cell viability/growth over Tamoxifen or C10 alone.…”

Neurolytic celiac plexus block enhances skeletal muscle insulin signaling and attenuates insulin resistance in GK rats

“…Obesity, a key risk factor for NIDDM, is associated with chronic inflammation and the release of inflammatory mediators such as TNF-α from adipose tissue; these inflammatory components may subsequently reduce insulin signaling and insulin-evoked glucose uptake into skeletal muscle, and may also damage insulin-producing pancreatic β cells (3)(4)(5)(6)11,12,(43)(44)(45)(46). As observed, TNF-α interferes with insulin receptor downstream signaling by phosphorylating IRS-1 at serine 307, resulting in reduced PI3K/Akt activity and GLUT4 translocation (32,33,(47)(48)(49).…”

“…Increasing evidence suggests that this pathway is a target of multiple metabolic signals and inflammatory cytokines associated with obesity (8,9). This pathway is also considered to represent a key risk factor in the development of NIDDM, including its actions upon FFAs, tumor necrosis factor α (TNF-α) and the pro-inflammatory interleukins IL-1β and IL-6 (10)(11)(12). Amongst other effects, these factors cause aberrant phosphorylation and dephosphorylation of InsR, IRS and Akt; this reduces the efficacy of insulin signaling, including insulin-evoked glucose transport (4,6,7,10,11).…”