Abstract Body (Do not enter title and authors here): Lipid metabolic abnormalities are associated with the incidence of the various cardiovascular diseases. Here, we identify that a novel seipin-Adipogenin complex plays a vital role in maintaining lipid homeostasis both in cells and adipose tissues.
Adipogenin (Adig) is a conserved microprotein highly expressed in adipose tissue and testis. Here, we identify Adig as a key regulator of lipid droplet (LD) formation in mammalian cells. We show that Adig directly interacts with seipin to form a stable, rigid complex. Using cryo-electron microscopy at ~3.0 Å overall resolution, we resolve the structure of the seipin-Adig complex and reveal that mammalian seipin assembles into two distinct oligomeric forms: undecamers and dodecamers. Notably, Adig selectively binds to the dodecameric form, enhancing seipin assembly by bridging and stabilizing adjacent subunits. Functionally, this complex reconfigures nascent LD development and promotes LD growth. In vivo, adipocyte-specific overexpression of Adig increases fat mass and enlarges LDs, whereas inducible deletion of Adig impairs triglyceride accumulation in brown adipose tissue. These findings establish Adig as a critical modulator of lipid storage through its structural and functional interaction with seipin.