309-LB: Cell-Permeable Truncated SOCS3 Competitively Inhibits the Interaction Between Endogenous SOCS3 and Leptin Receptor (ObR) to Overcome Leptin Resistance on JAK/STAT Signaling

Abstract

Aim: The abnormal control of leptin, an adipocyte-derived hormone controlling appetite, chronically enhances obesity. On binding to leptin receptor (ObR) expressed in hypothalamic neurons, leptin evokes JAK/STAT signaling, and induces the expression of suppressor of cytokine signaling 3 (SOCS3) as a negative feedback regulator to maintain the homeostatic balance between food intake and energy expenditure. However, due to excess leptin in obesity, increased levels of endogenous SOCS3 promotes leptin resistance and disables the appetite-control by leptin. We aim to develop cell-/tissue-permeable form of a truncated, trans-dominant SOCS3 protein (CP-?SOCS3) to antagonize leptin resistance caused by binding of endogenous SOCS3 to ObR and test its use as an anti-obesity and antidiabetic agent. Method: We have developed CP-?SOCS3 by fusing truncated SOCS3 with a hydrophobic cell-penetrating peptide, namely advanced macromolecule transduction domain. CP-?SOCS3 was tested using in vitro and in vivo leptin resistance models (in which endogenous SOCS3 is highly expressed) for the ability to intervene in JAK/STAT signaling and promote leptin sensitivity. Results: CP-?SOCS3 competitively bound at the p-Y985 of ObR against endogenous SOCS3 and significantly promoted leptin-induced JAK/STAT signaling in vitro. Diet-induced obese (DIO) mice treated with CP-?SOCS3 showed 12.1% body weight loss in 14 days (15 mg/kg, IV, daily injection). In addition, CP-?SOCS3 reduced blood cholesterol by 31% and improved glycemic control by 67% in the DIO mice. CP-?SOCS3 was delivered into brain by penetrating brain blood barrier. Conclusion: CP-?SOCS3 competitively suppressed the inhibitory action of endogenous SOCS3 on JAK/STAT signaling to enhance leptin sensitivity. Therefore, these results suggest that CP-?SOCS3 has a therapeutic potential as a protein-based anti-obesity and antidiabetic agent. Disclosure K. Lee: None.