Page 6 - N. Metabolism and metabolic diseases

[N. Metabolism and metabolic diseases-3]

Positive regulation Of JAK/STAT signaling with SOCS3-drived

cell-permeable binding domain to ObR induces anti-obesity

effect

Kuysook Lee¹, Jisook Jeon¹, Sujeong Kim¹, Hyeontae Kang¹, Youngsil Choi¹, Daewoong Jo¹

¹Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul 03929, Korea

Leptin, a hormone which regulates food intake and energy expenditure, is excessively expressed in obese patients,
promoting leptin resistance. We hypothesized that an exogenously delivered SOCS3 SH2 domain would compete
with SOCS3 for binding to Tyr985-phosphorylated ObR, and thereby maintain leptin-initiated JAK/STAT signaling.

Cell-permeable, truncated (Δ) SOCS3 and a sequence optimized-advanced macromolecule transduction domain
(aMTD) to deliver the protein into cells and tissues. Intracellular delivery of ΔSOCS3 was tested and proved for the

ability to enhance leptin signaling and sensitivity in the hypothalamus of diet-induced obese mice by penetrating
the blood-brain barrier. CP-ΔSOCS3 competitively bound to p-Tyr⁹⁸⁵ObR and blocked endogenous SOCS3 from

binding as assessed by increased levels of p-STAT3. 12.1% of body weight (in 14 days), fat volume (53.5%) and food
intake (29.2%) were also decreased in CP-ΔSOCS3-treated group compared to diluent group. Furthermore, treatment

group showed a significant increase in p-STAT3 and POMC in the hypothalamus. CP-ΔSOCS3 successfully enhances
leptin sensitivity which establishes the importance of SOCS3 in the biology of leptin signaling and resistance.

Therefore, CP-ΔSOCS3 might be used as a mechanism-specific weight-loss therapy.