Identification of trafficking proteins involved in adiponectin secretion

Background: Adiponectin is an insulin-sensitizing hormone which is produced and secreted exclusively by adipose tissue. After synthesis and multimerization of the single 30 kDa polypeptide within the endoplasmic reticulum, the adipokine proceeds through compartments of the Golgi apparatus and is subsequently released into the bloodstream. The ubiquitously expressed GTPase ARFRP1 (ADP-ribosylation factor-related protein 1) controls a scaffolding machinery at the trans-Golgi that is supposed to target intracellular vesicles to their correct destination. We therefore aim to elucidate the role of ARFRP1 on adipocyte function with a particular focus on adipokine secretion.

Methods: Deletion of Arfrp1 in adipose tissue was induced by treating mice with tamoxifen (Arfrp1 ^ad-ER-/-) before analyzing their phenotype. Additionally, 3T3-L1 adipocytes were studied following Arfrp1 suppression via an siRNA-mediated approach.

Results: Circulating adiponectin and adipsin, two adipokines known to have overlapping secretion pathways, were strikingly reduced in Arfrp1 ^ad-ER-/- mice, while plasma levels of WISP1, DPPIV and leptin were not affected. Despite no indications for an impaired multimerization in vivo and in vitro, Arfrp1-depleted 3T3-L1 adipocytes revealed an intracellular accumulation of adiponectin, especially in the fraction of high density microsomes, pointing towards a role of ARFRP1 and downstream effectors in the secretion process. Accordingly, Arfrp1 ^ad-ER-/- mice exhibited an impaired expansion of white adipose tissue, an increase in hepatic glucose production and elevated fasting blood glucose concentrations, which might be attributed to decreased plasma adiponectin levels.

Conclusion: The ARFRP1-mediated action at the trans-Golgi plays a particular role for maintaining plasma adiponectin levels thereby preserving systemic glucose homeostasis.

Funding: DZD, SFB958