Relationship status update for PTP1B and LepR: It׳s complicated★

The adipocyte-derived hormone leptin is an important regulator of systemic energy metabolism. Transported via the circulation to the brain in proportion to fat mass, leptin promotes its biological action through activation of the long form of the leptin receptor (LepRb). Accordingly, binding of leptin to the extracellular domain of LepRb promotes transphosphorylation of the LepRb-associated Janus kinase 2 (JAK2), which in turn phosphorylates other tyrosine residues (Tyr985, Tyr1077, Tyr1138) along the intracellular tail of LepRb in order to facilitate downstream signaling [1]. The protein tyrosine phosphatase 1B (PTP1B) is an important negative regulator of leptin action due to its ability to directly inhibit LepRb-Jak2 signaling (Figure 1). The relevance of PTP1B to regulate energy metabolism was first shown in mice with global