σ1B-adaptin sorts sortilin in adipose tissue regulating adipogenesis

Abstract

We describe altered sortilin sorting in AP-1/σ1B complex deficient adipocytes, which leads to the inhibition of adipogenesis. The AP-1 complex mediates protein sorting between the trans-Golgi network and endosomes. Vertebrates express three σ1-subunit isoforms: σ1A, σ1B and σ1C. σ1B −/− mice have impaired synaptic-vesicle recycling and a lipodystrophy. Sortilin is over-expressed in σ1B −/− adipose tissue and its over-expression in wild-type cells is sufficient to suppress adipogenesis. σ1B-specific binding of sortilin requires its DxxD-x12-DSxxxL motif. σ1B-deficiency does not lead to a block of sortilin transport out of a specific organelle, but the fraction which reaches lysosomes is reduced. Sortilin binds the DLK1 receptor, an inhibitor of adipocyte differentiation, and sortilin overexpression prevents DLK1 down-regulation, which leads to enhanced inhibition of adipogenesis. DLK1 and sortilin expression are not increased in the brain, although it is the tissue of highest σ1B and sortilin expression. Thus adipose tissue specific and σ1B-dependent routes for transport of sortilin exist and take part in the regulation of adipogenesis and adipose-tissue mass.