The role of ARFRP1 on adipocyte secretory capacity

Background:

Besides storing excess amounts of lipids, the adipose tissue displays a secretory capacity to mediate interorgan crosstalk. A dysregulated adipokine secretion profile, as observed under lipodystrophic or obese conditions, is associated with various metabolic disorders such as ectopic fat deposition and insulin resistance. The ubiquitously expressed GTPase ARFRP1 (ADP-ribosylation factor related protein 1) locates to trans-Golgi membranes where it is implicated in the targeting of intracellular cargo to downstream destinations. The major focus of this study was to elucidate particular trafficking pathways that are affected by ARFRP1 and influence adipokine secretion.

Methods:

Deletion of Arfrp1 in adipose tissue was induced by treating mice (Arfrp1 ^ad-ER-/-) with tamoxifen and analyzing their phenotype 5 weeks later. Additionally, HeLa and reporter HeLa M-C1 cells were studied following Arfrp1 suppression via siRNA.

Results:

ARFRP1-deficient HeLa cells revealed defective endosomal recycling of the transferrin/transferrin receptor complex, most likely at the level of cargo exocytosis rather than endosomal internalization. In contrast, constitutive secretion monitored in HeLa M-C1 cells was principally functioning in the absence of ARFRP1. Accordingly, circulating levels of adiponectin and adipsin were selectively reduced in Arfrp1 ^iAT-/- mice, whereas plasma levels of leptin and other adipokines were not changed. Presumably due to adiponectin deficiency, Arfrp1 ^iAT-/- mice showed a deteriorated hepatic insulin sensitivity, an increase in hepatic glucose production and elevated fasting blood glucose levels.

Conclusion:

The ARFRP1-mediated action as part of the vesicle trafficking machinery plays a particular role for maintaining plasma adiponectin levels, thereby preserving systemic glucose homeostasis.

Funding:

DZD, SFB958