s1B adaptin regulates adipogenesis by mediating the sorting of sortilin in adipose tissue

Here, we describe altered sorting of sortilin in adipocytes deficient for the s1B-containing AP-1 complex, leading to the inhibition of adipogenesis. The AP-1 complex mediates protein sorting between the trans-Golgi network and endosomes. Vertebrates express three AP1 s1 subunit isoforms – s1A, s1B and s1C (also known as AP1S1, AP1S2 and AP1S3, respectively). s1B-deficient mice display impaired recycling of synaptic vesicles and lipodystrophy. Here, we show that sortilin is overexpressed in adipose tissue from s1B mice, and that its overexpression in wild-type cells is sufficient to suppress adipogenesis. s1B-specific binding of sortilin requires the sortilin DxxD-x12-DSxxxL motif. s1B deficiency does not lead to a block of sortilin transport out of a specific organelle, but the fraction that reaches lysosomes is reduced. Sortilin binds to the receptor DLK1, an inhibitor of adipocyte differentiation, and the overexpression of sortilin prevents DLK1 downregulation, leading to enhanced inhibition of adipogenesis. DLK1 and sortilin expression are not increased in the brain tissue of s1B mice, although this is the tissue with the highest expression of s1B and sortilin. Thus, adipose-tissue-specific and s1B-dependent routes for the transport of sortilin exist and are involved in the regulation of adipogenesis and adipose-tissue mass.