Figure 2. Broad Overview of Relevant Inflammatory Pathways: JNK, JAK-STAT, and NF-κB Signaling.

Pattern recognition receptors (PRRs), expressed on immune and non-immune cells, can be activated by many different signals, including cytokines. A) c-Jun N-terminal kinase 3 (JNK3) also known as mitogen-activated protein kinase (MAPK)-10, is activated when inflammatory cytokines begin a kinase signaling cascade via a MAPK kinase (MAPKK) and MAPKK kinase (MAPKKK) (solid line). JNK may also be activated by reactive oxygen species (ROS) produced by mitochondria. Activated JNK phosphorylates transcription factors, including activator protein-1 (AP-1), which then regulate the inflammatory response. AP-1 also has a response element in the promoter region of suppressor of cytokine signaling 3 (SOCS3) (dashed line). B) When a ligand, such as leptin, binds to the receptor, two receptor-associated Janus family of tyrosine kinases (JAK) proteins are brought in close contact and transphosphorylate, creating a docking site for the cytoplasmic JAK-signal transducer and activator of transcription (STAT) proteins. The JAK proteins then phosphorylate the STAT proteins, which dimerize and translocate to the nucleus to regulate transcription for satiety signaling pathways (e.g., pro-opiomelanocortin, POMC) and the inflammatory response. SOCS3 inhibits the JAK-STAT pathway and down-regulates leptin signaling. C) The PRR for NF-κB, typically Toll-like receptor 4 (TLR4), activates IκB kinase (IKK), a protein complex that phosphorylates the protein IκB, releasing it from the NF-κB complex. ROS may also activate IKK. NF-κB then translocates to the nucleus to activate gene transcription of many pro-inflammatory cytokines. Increased activation of NF-κB in POMC neurons has also been associated with increased expression of SOCS3 (dashed line). Created with BioRender.com.