310-LB: Intracellular Protein Therapy with Truncated SOCS3 Suppresses Obesity

Abstract

Aim: Therapeutic molecule systemic delivery technology (TSDT), a platform for the discovery/development of new medicinal drugs, is enabled with a new generation of hydrophobic cell-penetrating peptides (CPPs), namely advanced macromolecule transduction domains (aMTDs). Leptin is an adipocyte-derived hormone that suppresses food intake and stimulates energy expenditure, leading to a reduction in stored body fat. However, patients with obesity have high levels of leptin, resulting in expression of suppressor of cytokine signaling (SOCS) 3 which is a negative feedback regulator of janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling initiated by the leptin receptor (ObR). Leptin resistance arises in part from the inhibition of leptin-initiated JAK/STAT signaling by SOCS3 binding to the phosphorylated Tyr-985 of ObR. We developed a cell-permeable, trans-dominant SOCS3 protein (CP-?SOCS3) to antagonize endogenous SOCS3 binding at P-Tyr-985 of ObR for use as an anti-obesity agent. Method: We have developed CP-?SOCS3 by fusing the SOCS3 SH2-domain (46∼177 AA) to an aMTD sequence and tested the protein for the ability to enhance leptin induced ObR signaling, prolong leptin sensitivity and suppress weight gain in murine obesity models. Result: CP-?SOCS3 interacted with ObR and enhanced leptin signaling (activation of STAT3) in mouse hypothalamus cells (mHypoA2/21 cells). In addition, CP-?SOCS3 showed 14.9% body weight loss in 14 days (15 mg/kg, daily, IV) in high fat diet-induced obese (DIO) mice. Food intake (33.6%), epididymal fat mass (34.1%) and serum leptin (59.5%) also decreased as compared to the mice treated with diluent. Furthermore, CP-?SOCS3 positively regulated leptin-initiated JAK/STAT signaling in DIO mice. Conclusion: These results provide further validation of TSDT as a platform to develop protein-based biotherapeutics and suggest that CP-?SOCS3 has potential as a protein-based anti-obesity agent. Disclosure K. Lee: None.