Convergent trafficking pattern of leptin after endocytosis mediated by ObRa-ObRd.

The cellular effects of leptin are dependent on the receptor subtypes that mediate the signaling and fate of endocytosed leptin inside the cells. In this study, we examined the differences in receptor expression, endocytosis, intracellular degradation, and exocytosis of a trace amount of leptin in cells overexpressing ObRb and short forms of the leptin receptor. The relative contribution of proteasomes and lysosomes in the intracellular fate of leptin was also determined. There were three unusual findings: (1) all receptor subtypes could mediate the binding and endocytosis of leptin, although ObRb was expressed at a lower level than ObRa, ObRc, and ObRd after transient transfection. This indicates that ObRb can be a transporting receptor. (2) Once internalized, the intracellular degradation pattern and exocytosis of leptin were independent of the receptor subtype. (3) Endocytosed leptin could remain intact for at least 1 h. This stability was further enhanced by inhibition of lysosomal activity. Thus, the intracellular pool of intact leptin may allow prolonged biological functions for this adipokine.