A model for modulation of leptin activity by association with clusterin.

Transport, biological action, and clearance of leptin are subject to modulation by plasma components responsible for the formation of the so-called "bound" fraction of serum leptin. Candidates for modulators have been identified previously, but mechanisms for their action, and thus their physiological roles, have remained unclear. Here we have obtained evidence for a role of serum-borne clusterin in leptin biology and have delineated a possible mechanism for its action. We demonstrate complex formation between clusterin and leptin by several approaches and show that the binary complex retains the ability to transduce the leptin signal via binding to the leptin receptor and activation of the Janus kinase/signal transducer and activator of transcription pathway. The interaction of leptin with clusterin does not require additional serum components. Furthermore, and importantly for modulation of the bioactivity of leptin, uptake of leptin present in the complex can be mediated by members of the low density lipoprotein (LDL) receptor family, i.e., apolipoprotein receptor type-2 and the very LDL receptor, which here are shown to efficiently endocytose both free and leptin-associated clusterin. Thus, bioavailability of leptin at a given tissue site may be determined by the levels of clusterin and/or by the relative distribution of certain relatives of the LDL receptor vis-à-vis active leptin receptors.