Obesity, Inflammation, Toll-Like Receptor 4 and Fatty Acids

Abstract

Obesity leads to an inflammatory condition that is directly involved in the etiology of cardiovascular diseases, type 2 diabetes mellitus, and certain types of cancer. The classic inflammatory response is an acute reaction to infections or to tissue injuries, and it tends to move towards resolution and homeostasis. However, the inflammatory process that was observed in individuals affected by obesity and metabolic syndrome differs from the classical inflammatory response in certain respects. This inflammatory process manifests itself systemically and it is characterized by a chronic low-intensity reaction. The toll-like receptor 4 (TLR4) signaling pathway is acknowledged as one of the main triggers of the obesity-induced inflammatory response. The aim of the present review is to describe the role that is played by the TLR4 signaling pathway in the inflammatory response and its modulation by saturated and omega-3 polyunsaturated fatty acids. Studies indicate that saturated fatty acids can induce inflammation by activating the TLR4 signaling pathway. Conversely, omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, exert anti-inflammatory actions through the attenuation of the activation of the TLR4 signaling pathway by either lipopolysaccharides or saturated fatty acids.

Keywords: fatty acids; inflammation; obesity; toll-like receptor 4.

Figure 1

Interaction between M1 and M2 macrophages and adipocytes. Abbreviations: IL, interleukin; MCP, monocyte chemotactic protein; NEFAs, non-esterified fatty acids; TNF, tumor necrosis factor.

Figure 2

Toll-like receptor 4 (TLR4) induced signaling activates the transcription factor NFκB. LBP: LPS-binding protein; LPS: lipopolysaccharides; IRAK: IL-1 receptor associated kinase; TRAF6: TNF receptor associated factor 6; MAPK: mitogen activated protein kinase; IKK: inhibitor of nuclear factor kappa-B kinase; iNOs: inducible nitric oxide synthase.

Figure 3

Molecular mechanism of the effects of saturated (16:0) and omega-3 polyunsaturated fatty acids (EPA, DHA) on the TLR4 and NFkB pathways. The arrows → indicate activation and the arrows Ⱶ indicate inhibition. Abbreviations: TNFα, Tumor necrosis factor; TNFR1, Tumor necrosis factor receptor 1; LPS, Lipopolysaccharides; 16:0, palmitic acid; TLR4, Toll-like receptor 4; GPR120, G-protein coupled receptor 120; EPA, eicosapentaenoic acid; DHA, Docosahexaenoic acid; IRS-1, Insulin receptor substrate 1; Ser-P, phosphorylated serine residues; PPARγ, Peroxisome proliferator-activated receptor gamma; JNK, c-Jun N-terminal kinases; IKK β, inhibitor of nuclear factor kappa-B kinase subunit beta; IkB, NFKB Inhibitor; P, phosphate; AP-1, Activator protein 1.