The role of the Golgi apparatus on adipocyte secretory function

Abstract

Background/Aim: Circulating adiponectin, which has insulin sensitizing effects on liver and muscle, is synthesized at the endoplasmic reticulum and proceeds through compartments of the Golgi apparatus prior to its secretion into the bloodstream. We have recently observed that postnatal adipocyte-specific deletion of the trans-Golgi associated GTPase ARFRP1 (ADP-ribosylation factor-related Protein1), which is required for organizing specific protein scaffolds in this compartment, resulted in elevated blood glucose levels and increased hepatic glucose production in the absence of ectopic fat storage. We therefore aim to elucidate the detailed machanism of ARFRP1 and its downstream effectors in regulating adipocyte secretory function. Methods: Adipose tissue morphology and adipocyte function were analyzed in inducible fat-specific Arfrp1 knockout mice (Arfrp1ad-ER-/-), in which ARFRP1 deletion was initiated at five weeks of age. Results: Five weeks after initiating Arfrp1 deletion mice exhibited an impaired expansion of adipose tissue marked by significantly lower body fat content compared to control mice. This effect was accelerated ten weeks after Arfrp1 deletion resulting in fibrosis, apoptosis and macrophage infiltration. Initially two weeks after Arfrp1 deletion, when adipose tissue mass was equal and adipocyte morphology was inconspicuous, plasma adiponectin levels already dropped, while plasma leptin levels were unaltered, suggesting that the ARFRP1 cascade may be directly involved in adiponectin secretion. Accordingly, adiponectin secretion was significantly impaired after depletion of the ARFRP1 downstream effectors golgin-245 and golgin-97 in 3T3-L1 adipocytes. Conclusion: The ARFRP1 action at the trans-Golgi plays a particular role for adiponectin either by regulating the process of secretion, multimerization or degradation. Funding: BMBF: DZD,82DZD00301, DFG: SFB958