Figure 1. Neuronal Leptin Receptor Activation and Inactivation.

A. In the resting state, the long form leptin receptor (LepRb) exists as a homodimer at the plasma membrane¹⁵³. The tyrosine kinases Janus Kinase (JAK2) and Src-Family-Kinases (SFKs), and the JAK2-binding protein SH2B, are constitutively associated with membrane-proximal regions of LepRb^154,155. B. Upon ligand (leptin) binding to LepRb (1:1 stoichiometry¹⁵⁶), the two receptor subunits undergo a conformational change resulting in transphosphorylation and transactivation of JAK2 and SFKs proteins^157,158. SH2B enhances JAK2 enzymatic activity¹⁵⁹. Activated JAK2 and possibly SFK enzymes, then phosphorylate LepRb tyrosine (Tyr) residues⁵⁸. Three cytoplasmic Tyr residues of the murine LepRb acts as binding sites for SH2-domain containing proteins. Specifically, SHP2 principally binds to pY985, STAT5 to pY1077 and STAT3 to pY1338^160,161. LepRb-bound SHP2, STAT3 and STAT5 proteins then become phosphorylated by JAK2 and SFKs. Additional downstream signalling proteins and pathways include PI3K-Akt; GRB2-Erk1/2^58,160,162; p90RSK⁵⁸; p70RSK and ribosomal S6 proteins; and the forkhead box-containing protein O1 (FoxO1) ^163,164. These enzymes and pathways ultimately exert regulation of cellular processes, including transcriptional control (socs3^165,166, pomc^167,168, cFos⁵⁸, carboxypeptidase E (cpe)¹⁶⁹, as well as agrp and npy ¹⁶⁸), translational control^170–172, and neuronal activity and firing^109,173. C. LepRb is inactivated at proximal steps by PTP1B/PTPN1, a tyrosine phosphatase that directly dephosphorylates JAK2⁷⁶. Furthermore, SOCS3 acts to inhibit JAK2 activity by binding directly to JAK2 or indirectly by first binding to Tyr985 or Tyr 1077 of LepRb^68,80,161. Finally, yet unidentified protein tyrosine phosphatases are predicted to directly dephosphorylate LepRb and SFKs.