Activation of the insulin signaling pathway leads to FOXO1 phosphorylation, resulting in nuclear exclusion and inhibition of FOXO1-mediated activation/repression of target genes. By removing FOXO1 repression, insulin increases the anorexigenic tone via induced POMC gene expression in POMC neurons with simultaneous suppressed AgRP/NPY expression in AgRP neurons. Binding of leptin to the leptin receptor activates and recruits STAT3. Tyrosine phosphorylation triggers dimerization of STAT3 and translocation to the nucleus, where the STAT3 complex induces POMC gene expression in POMC neurons and suppresses AgRP/NPY in AgRP neurons. TNF-α binding promotes the trimerization of the TNF receptor, which promotes the assembly of a signaling complex that activates JNK and inhibits cellular insulin signaling. In addition, TNF signaling triggers activation of NF-κB. In the TLR4 signaling pathway, MyD88 serves as a scaffold protein for downstream signaling molecules. NF-κB dimers are sequestered in the cytoplasm by the inhibitor of NF-κB α (IκBα). Phosphorylation by the IKK complex and subsequent proteolysis of IκBα leads to the release and nuclear translocations of NF-κB. NF-κB heterodimer RelA and p50 bind to motifs in the promoter of targets genes, such as SOCS3, a common inhibitor of insulin and leptin signaling, and proinflammatory genes. Induction of ceramides leads to increased phosphorylation and localization of PKC with caveolin-enriched lipid microdomains to inactivate Akt.