Article

Adiponectin and Leptin are Secreted Through Distinct Trafficking Pathways in Adipocytes

Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 03/2008; 1782(2):99-108. DOI: 10.1016/j.bbadis.2007.12.003
Source: PubMed

ABSTRACT

Adiponectin and leptin are two adipokines secreted by white adipose tissue that regulate insulin sensitivity. Previously we reported that adiponectin but not leptin release depends on GGA-coated vesicle formation, suggesting that leptin and adiponectin may follow different secretory routes. Here we have examined the intracellular trafficking pathways that lead to the secretion of these two hormones. While adiponectin and leptin displayed distinct localization in the steady-state, treatment of adipocytes with brefeldin A inhibited both adiponectin and leptin secretion to a similar level, indicating a common requirement for class III ADP-ribosylating factors and an intact Golgi apparatus. Adiponectin secretion was significantly reduced by endosomal inactivation in both 3T3L1 and rat isolated adipocytes, whereas this treatment had no effect on leptin secretion. Importantly, endosomal inactivation completely abolished the insulin stimulatory effect on adiponectin release in rat adipocytes. Confocal microscopy studies revealed colocalization of adiponectin with endogenous rab11 a marker for the recycling endosome, and with expressed rab5-GFP mutant (rab5Q75L) a marker for the early endosome compartment. Colocalization of adiponectin and rab5Q75L was increased in endosome inactivated cells. Consistent with these findings adiponectin secretion was reduced in cells expressing mutants of Rab11 and Rab5 proteins. In contrast, expression of an inactive (kinase dead) mutant of Protein Kinase D1 moderately but significantly inhibited leptin secretion without altering adiponectin secretion. Taken together, these results suggest that leptin and adiponectin secretion involve distinct intracellular compartments and that endosomal compartments are required for adiponectin but not for leptin secretion.

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    • "As a classically transported adipokine, leptin secretion is abolished by brefeldin A treatment. The serine/threonine protein kinase D1 (PKD1) has been proposed to mediate the fission at the trans-Golgi network of leptin transport vesicles to the plasma membrane (Xie et al. 2008). Leptin secretion seems to take place through both constitutive and regulated secretory pathways. "
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    • "3T3-L1 adipocytes were obtained from the American Type Culture Collection (Manassas, VA). Adipocytes were cultured and differentiated as described previously [25], [26]. "
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    • "The protein moves through the Golgi and trans- Golgi network where an important pool of adiponectin is packaged into GGA1 (Golgi localizing γ-adaptin ear homology domain ADP ribosylating factor -ARF-binding) coated vesicles [14] and delivered to endosomes [14]. Other adipokines such as adipsin also rely on the endosomal compartment for their release (Clarke et al 2006; Millar et al. 2000), whereas leptin does not (Xie et al 2008). Adiponectin was found to colocalize with rab11, a marker of the Endosomal Recycling Compartment (ERC) [15] [16]. "
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    ABSTRACT: Adiponectin is an adipokine secreted by white adipocytes involved in regulating insulin sensitivity in peripheral tissues. Secretion of adiponectin in adipocytes relies on the endosomal system, however, the intracellular machinery involved in mediating adiponectin release is unknown. We have previously reported that intracellular adiponectin partially compartmentalizes with rab 5 and rab11, markers for the early/sorting and recycling compartments respectively. Here we have examined the role of several rab11 downstream effector proteins (rab11 FIPs) in regulating adiponectin trafficking and secretion. Overexpression of wild type rab11 FIP1, FIP3 and FIP5 decreased the amount of secreted adiponectin expressed in HEK293 cells, whereas overexpression of rab11 FIP2 or FIP4 had no effect. Furthermore shRNA-mediated depletion of FIP1 enhanced adiponectin release whereas knock down of FIP5 decreased adiponectin secretion. Knock down of FIP3 had no effect. In 3T3L1 adipocytes, endogenous FIP1 co-distributed intracellularly with endogenous adiponectin and FIP1 depletion enhanced adiponectin release without altering insulin-mediated trafficking of the glucose transporter Glut4. While adiponectin receptors internalized with transferrin receptors, there were no differences in transferrin receptor recycling between wild type and FIP1 depleted adipocytes. Consistent with its inhibitory role, FIP1 expression was decreased during adipocyte differentiation, by treatment with thiazolidinediones, and with increased BMI in humans. In contrast, FIP1 expression increased upon exposure of adipocytes to TNFα. In all, our findings identify FIP1 as a novel protein involved in the regulation of adiponectin trafficking and release.
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