Low expression level of OB-Rb results from constitutive translocational attenuation attributable to a less efficient signal sequence

OB-Rb is a crucial factor for leptin signaling. This study was initially motivated by the observation that OB-Rb expression is constitutively inhibited in the early secretory pathway. Our analyses reveal that OB-Rb contains a less hydrophobic, but functionally active N-terminal signal sequence. Constitutive translocational attenuation attributable to a less efficient signal sequence proved to be a reason for low protein level of OB-Rb. By contrast, enhanced signal sequence efficiency rescues translocation and cell surface expression of OB-Rb, and eventually potentiates leptin signaling. These observations provide considerable insight into the therapeutic enhancement of OB-Rb translocation as a potential strategy for leptin resistance.