Ajuwon, K. M. & Spurlock, M. E. Palmitate activates the NF-B transcription factor and induces IL-6 and TNF expression in 3T3-L1 adipocytes. J. Nutr. 135, 1841-1846

Department of Animal Sciences, Center for Comparative Medicine, Purdue University, West Lafayette, IN 47907-2054, USA.
Journal of Nutrition (Impact Factor: 3.88). 08/2005; 135(8):1841-6.
Source: PubMed


Fatty acids and their metabolites regulate gene expression and immunological pathways. Furthermore, obese individuals frequently have increased circulating fatty acid concentrations, and localized inflammation in adipose tissue may facilitate the systemic inflammation associated with the insulin resistance of obesity. Although palmitate induces inflammation (i.e., activates proinflammatory pathways) in myotubes, the effects of fatty acids on inflammatory processes in adipocytes have not been established. Therefore, we examined the potential for palmitate, laurate, and docosahexaenoic acid (DHA) to modulate inflammation in 3T3-L1 adipocytes. Palmitate, but not DHA or laurate, induced nuclear factor κB (NF-κB)-driven luciferase activity and interleukin-6 (IL-6) expression (P < 0.05). Inhibition of fatty acyl Co-A synthase (FACS) with triacsin C suppressed palmitate-induced NF-κB activation (P < 0.05), but caused an additive increase in palmitate-induced IL-6 expression (P < 0.05). Disrupting mitogen-activated protein kinase/Erk kinase (MEK) and protein kinase C (PKC) activity with U0126 and Bisindolylmaleimide (Bis), respectively, suppressed palmitate-induced IL-6 expression (P < 0.05), but had no effect on NF-κB reporter gene activity (P > 0.05). However, the phosphoinositide-3 kinase (PI3K) inhibitor, wortmannin, alone and additively with palmitate, activated the NF-κB reporter gene and induced IL-6 expression (P < 0.05). Palmitate also induced the mRNA expression of tumor necrosis factor α(TNFα) (P < 0.05), but the increase in mRNA abundance was not reflected in a greater protein concentration in the media (P > 0.05). These data indicate that palmitate induces inflammation in adipocytes, and that this is not a generalized effect of all SFA. Furthermore, PI3K may act constitutively to suppress inflammation. Consequently, inhibition of this enzyme may promote and exacerbate the inflammation in adipose tissue that is associated with obesity and insulin resistance.

Download full-text


Available from: Kolapo M Ajuwon,
43 Reads
  • Source
    • "We induced insulin-resistance in differentiated 3T3-L1 cells using palmitate following established protocol (Ajuwon and Spurlock, 2005; Van Epps-Fung et al., 1997). Palmitate treated cells exhibited compromised insulin response which was restored by CDCA as determined by glucose uptake assay (Figure 1A). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adipose tissue secretes adipokines that regulate insulin sensitivity in adipocytes and other peripheral tissues critical to glucose metabolism. Insulin resistance is associated with severe alterations in adipokines characterized by release of increased pro-inflammatory cytokines and decreased anti-inflammatory cytokines from adipose tissue. The role of Farnesoid X receptor (FXR) activation on adipokines in relation to adipose tissue inflammation and insulin resistance is not completely explored. For the first time, we have evaluated the ability of Chenodeoxycholic acid (CDCA), an endogenous FXR ligand, in restoring the disturbance in adipokine secretion and insulin resistance in palmitate treated 3T3-L1 cells and adipose tissues of High fat diet (HFD) rats. CDCA suppressed several of the tested pro-inflammatory adipokines (TNF-α, MCP-1, IL-6, Chemerin, PAI, RBP4, resistin, vaspin), and enhanced the major anti-inflammatory and insulin sensitizing adipokines (adiponectin, leptin). CDCA suppressed the activation of critical inflammatory regulators such as NF-κB and IKKβ which are activated by palmitate treatment in differentiated cells and HFD in rats. We show the altered adipokines in insulin resistance, its association with inflammatory regulators, and the role of CDCA in amelioration of insulin resistance by modulation of adipokines. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 07/2015; 414:19-28. DOI:10.1016/j.mce.2015.07.012 · 4.41 Impact Factor
  • Source
    • "The SFA (rich in palmitate) expands WAT and increases inflammation and apoptosis through oxidative or endoplasmic reticulum stress, generation of ceramide and reactive oxygen species, and protein kinase C signaling [63]. Additionally, palmitate increases the expression and secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-10 [64] [65] and activates toll-like receptor (TLR) signaling in murine adipocytes [66] [67] [68] and macrophages [65] [66] [68] [69], leading to nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) activation and cytokine production. Davis et al. showed that TLR4 knockout mice were protected against the adverse effects of eating an HF diet rich in palmitate [70]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: During pregnancy and/or lactation, maternal nutrition is related to the adequate development of the fetus, new-born and future adult, likely by modifications in fetal programming and epigenetic regulation. Fetal programming is characterised by adaptive responses to specific environmental conditions during early life stages, which may alter gene expression and permanently affect the structure and function of several organs and tissues, thus influencing the susceptibility to metabolic disorders. Regarding lipid metabolism during the first two trimesters of pregnancy, the maternal body accumulates fat, whereas in late pregnancy, the lipolytic activity in the maternal adipose tissue is increased. However, an excess or deficiency of certain fatty acids may lead to adverse consequences to the fetuses and new-borns. Fetal exposure to trans fatty acids appears to promote early deleterious effects in the offspring’s health, thereby increasing the individual risk for developing metabolic diseases throughout life. Similarly, the maternal intake of saturated fatty acids seems to trigger alterations in the liver and adipose tissue function associated with insulin resistance and diabetes. The polyunsaturated fatty acids (PUFA), particularly long chain PUFA (LC-PUFA-AA, EPA and DHA), play an important and beneficial physiologic role in the offspring who receive this fatty acid during critical periods of development. Therefore, the maternal nutritional condition and fatty acid intake during pregnancy and/or lactation are critical factors that are strongly associated with normal fetal and postnatal development, which influence the modifications in fetal programming and in the individual risk for developing metabolic diseases throughout life.
    The Journal of Nutritional Biochemistry 10/2014; 26(2). DOI:10.1016/j.jnutbio.2014.10.001 · 3.79 Impact Factor
  • Source
    • "Our findings contrast previous chronic studies (24 to 48 h) in mature 3T3-L1 adipocytes that demonstrated increased MCP-1 [18], IL-6 [17] and TNF-α [33] gene expression levels via NF-κB activation with palmitic acid treatment. Another key SFA, stearic acid, has also been shown to exert pro-inflammatory effects after 24 hours [18], however the shorter chain SFA, lauric acid [17] and MUFA, oleic acid [18], [33] reportedly have no effect on these markers in mature adipocytes even over longer periods of time. Despite the link between myristic acid and chronic disease [50], there are surprisingly few studies, if any, which have examined the inflammatory effects of this FA in vitro. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Preadipocytes contribute to the inflammatory responses within adipose tissue. Whilst fatty acids are known to elicit an inflammatory response within adipose tissue, the relative contribution of preadipocytes and mature adipocytes to this is yet to be determined. We aimed to examine the actions of common dietary fatty acids on the acute inflammatory and adipokine response in 3T3-L1 preadipocytes and differentiated mature adipocytes. Gene expression levels of key adipokines in 3T3-L1 preadipocytes and adipocytes were determined following incubation with palmitic acid, myristic acid or oleic acid and positive inflammatory control, lipopolysaccharide for 2 and 4 h. Inflammatory kinase signalling was assessed by analysis of nuclear factor-κB, p38-mitogen-activated protein kinase and c-jun amino-terminal kinase phosphorylation. Under basal conditions, intracellular monocyte chemoattractant protein-1 and interleukin-6 gene expression levels were increased in preadipocytes, whereas mature adipocytes expressed increased gene expression levels of leptin and adiponectin. Fatty acid exposure at 2 and 4 h increased both monocyte chemoattractant protein-1 and interleukin-6 gene expression levels in preadipocytes to greater levels than in mature adipocytes. There was an accompanying increase of inhibitor of κB-α degradation and nuclear factor-κB (p65) (Ser536) phosphorylation with fatty acid exposure in the preadipocytes only. The current study points to preadipocytes rather than the adipocytes as the contributors to both immune cell recruitment and inflammatory adipokine secretion with acute increases in fatty acids.
    PLoS ONE 06/2014; 9(6):e99382. DOI:10.1371/journal.pone.0099382 · 3.23 Impact Factor
Show more