Aim: Insulin resistance, the reduced ability of tissues to respond to insulin, is a defining feature of T2DM. Leptin, hormone signals though the JAK/STAT pathway and enhances insulin sensitivity. Leptin signaling is negatively regulated by suppressor of cytokine signaling 3 (SOCS3) that binds to the leptin receptor and promotes leptin resistance. Prolonged leptin stimulation is further associated with hyperinsulinemia and insulin resistance. To investigate the interplay between leptin and insulin signaling with the goal of suppressing leptin-induced insulin resistance in pathological settings we developed a cell-permeable dominant-interfering SOCS3 [(∆) SOCS3].

Method: Cell-permeable, dominant-interfering ΔSOCS3 protein consists of the SOCS3 SH2 domain, a sequence optimized-advanced macromolecule transduction domain (aMTD) to deliver the protein into cells and tissues to facilitate soluble purification, biologically active proteins. Intracellular delivery of ΔSOCS3 was tested in diet-induced obese (DIO) mice to evaluate the increment of insulin sensitivity and glucose control.

Result: CP-ΔSOCS3 was delivered into cells and tissues including brain, liver, spleen and lung. Insulin pretreatment attenuates insulin-mediated Akt signaling in HepG2 cells; whereas, insulin sensitivity was restored by CP-ΔSOCS3. DIO mice treated with CP-ΔSOCS3 showed 12.1% body weight loss in 14 days. In addition, groups of mice were examined with the glucose tolerance test. Blood glucose at 2 hrs decreased by 66.7% and area under curve decreased by 40.3% in treatment group as compared to the diluent group. CP-ΔSOCS3 also reduced blood cholesterol by 31% and fatty liver by 92.6% and was accompanied by significant increases in Akt phosphorylation in the hypothalamus, fat and muscle consistent with enhanced insulin sensitivity.

Conclusion: CP-ΔSOCS3 has therapeutic effect on obesity and blood glucose control. These results suggest CP-ΔSOCS3 may provide a mechanism-specific therapy for T2DM.


J. Jeon: None. K. Lee: None. S. Kim: None. H. Kang: None. J. Kwak: None. Y. Choi: None. D. Jo: None.

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