The Macrophage–Adipocyte Crosstalk in Metabolically challenged Adipose Tissue. Activation of macrophage TLR4 by SFAs induces the expression of proinflammatory cytokines, such as IL-1β, IL-6 and TNF-α. Binding of proinflammatory cytokines to their corresponding receptors on adipocytes induces the expression of SOCS3 and activates JNK and mTORC1. Stimulation of SOCS3 leads to proteasomal degradation of IRS1. Activated JNK and mTORC1 block IRS1 downstream signaling by promoting phosphorylation of inhibitory serine residues on IRS1. The concomitant insulin signaling inhibition promotes the establishment of insulin resistance in the AT. (Created with BioRender.com on 19 October 2022). Abbreviations: SFAs, saturated fatty acids; TLR4, Toll-like receptor 4; MyD88, myeloid differentiation factor 88; IRAK1/4, IL-1 receptor-associated kinase 1 and 4; TRAF6, tumor necrosis factor receptor associated factor 6; IKK, IκB kinase; IκB, inhibitor κB kinase; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; TSC1/2, tuberous sclerosis protein complex 1 and 2; mTORC1, mammalian target of rapamycin complex; GLUT4, glucose transporter type 4; IR, insulin receptor; IRS, Insulin receptor substrate; PI3K, phosphoinositide 3-kinase; JNK, Jun N-terminal kinase; SOCS3, suppressor of cytokine signaling 3; IL-1β, interleukin 1β; IL-6, interleukin 6; TNF-α, tumor necrosis factor α; CR, cytokine receptor; AT, adipose tissue.