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Figure 2 Theoretical Cellular and Molecular Mechanisms of Leptin Pathophysiology
(A) In leptin-resistant tissue (e.g., hypothalamic cell illustrated), serum leptin-interacting proteins (SLIPs) and soluble leptin receptor (SLR) may bind circulating adipose-secreted leptin and inhibit its action. Free leptin engages the long form of its receptor (Ob-Rb), which homodimerizes. Intracellularly, activated janus kinase 2 (JAK2) phosphorylates a specific tyrosine docking site (Tyr1138) on Ob-Rb. Signal transduction and translation protein 3 (STAT3) recognizes and binds to activated Tyr1138 via its src homology 2 (SH2) domain. The Ob-Rb/JAK2 complex activates STAT3, which homodimerizes, then translocates to the nucleus to modulate gene transcription. STAT3 up-regulates expression of suppressor-of cytokine-signaling-3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B), which block JAK2 phosphorylation. It is thought that central leptin resistance promotes obesity, driving greater hyperleptinemia. (B) In nonleptin-resistant tissue (e.g., immune cell illustrated) exposed to hyperleptinemia, Ob-Rb may signal excessively through multiple signaling pathways, including JAK/STAT, insulin receptor substrate-2/phosphatidylinositol 3-kinase (IRS-2/PI3K), and nitric oxide that may ultimately promote cardiovascular disease (CVD) through tissue-specific mechanisms.
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