Lipids as signaling molecules that regulate metabolism

Lipids as signaling molecules that regulate metabolism. Several signaling lipids, including fatty acids, fatty acid esters of hydroxy fatty acids (FAHFAs), diacylglycerol (DAG), and ceramides, regulate insulin sensitivity. (a) Saturated fatty acids (SFAs) activate Toll-like receptor 4 (TLR4), possibly via its co-receptor, myeloid differentiation protein 2 (MD2), which, through the adaptor proteins TIR domain-containing adaptor-inducing interferon-β (TRIF) and myeloid differentiation primary response protein MYD88, increases the activity of pro-inflammatory transcription factors. TRIF activation promotes the nuclear translocation of interferon regulatory factor 3 (IRF3) to increase the expression of cytokines. MYD88 activation increases phosphorylation of inhibitor of nuclear factor-κB (NF-κB) kinase (IKKβ), which further phosphorylates inhibitor of NF-κB (IκB), leading to nuclear translocation of NF-κB to increase pro-inflammatory cytokine expression. MYD88 also activates Jun N-terminal kinase (JNK) to increase the activity of transcription factor activator protein 1 (AP1), thereby altering the expression of cytokines. Proinflammatory cytokines, through their receptors, further activate these proinflammatory transcription factors to establish a positive feedback loop for sustained inflammation. SFA-activated TLR4 and cytokine production impair insulin signaling through IKKβ and JNK activation. SFA-mediated activation of endoplasmic reticulum (ER) stress, the SRC–JNK pathway, and the incorporation of SFAs into DAG and ceramides also impair insulin signaling by inhibiting phosphorylation of the insulin receptor, insulin receptor substrate 1 (IRS1) or AKT. Polyunsaturated fatty acids (PUFAs) exert anti-inflammatory effects by activating G-protein-coupled receptor 120 (GPR120), which recruits β-arrestin 2 and sequesters TAK1-binding protein 1 (TAB1) to inhibit the TAK1-mediated activation of JNK and IKKβ. PUFA, FAHFAs, and resolvins may exert anti-inflammatory effects by activating G-protein-coupled receptors (GPCRs) in antigen-presenting cells such as macrophages to inhibit cytokine production. (b) DAG and ceramide may induce insulin resistance. DAG accumulates ectopically in insulin-resistant muscle and liver. In muscle, DAG-activated protein kinase Cθ (PKCθ) promotes the phosphorylation of IRS1 on Ser1101 in mice, impairing IRS1 phosphorylation on tyrosine and attenuating insulin signaling. In the liver, DAG-activated PKCε promotes phosphorylation of IR on Thr1160 to suppress insulin signaling. Elevated DAG impairs glucose uptake via reduced insulin-responsive glucose transporter 4 (GLUT4) in muscle, and glucose output via GLUT2 from the liver is increased; these changes induce hyperglycemia. Ceramides contribute to hyperglycemia by activating protein phosphatase 2 A (PP2A), which dephosphorylates AKT, stimulating PKCλ and PKCζ, which prevent AKT membrane association, thereby inhibiting AKT activity. Reproduced from Yang et al. (2018) [108]

Publication

Cellular Senescence and Extracellular Vesicles in the Pathogenesis and Treatment of Obesity—A Narrative Review (2024) Yicong Liang, et al. Int J Mol Sci. 2024 Jul;25(14). Figure: F10. Homo sapiens

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