Increased free fatty acid flux from white adipocytes exacerbates insulin resistance and increases the risk of its progression to type 2 diabetes. Distinct intracellular organelles called lipid droplets (LDs) in adipocytes play a key role in storing fatty acids (FAs) as triglycerides (TGs), hence protecting against FA-induced lipotoxicity. A highly coordinated cascade of LD-associated proteins and lipases is known to regulate the catabolism of stored TGs in LDs, but the molecular components of LDs that determine their dynamics and TG storing capacity in adipocytes remains understudied. Previously, we showed that Fat specific protein 27 (FSP27) is a lipid droplet associated protein that is positively associated with insulin sensitivity in humans, and plays a crucial role in lipid droplet dynamics by clustering and then fusion of LDs. The present investigation was designed to identify the molecular mechanism through which FSP27 mediates LD trafficking to regulate the initial step of LD clustering—a prerequisite of LD fusion. We found that a direct interaction between FSP27, Vimentin and Rab18, and FSP27-mediated activation of Rab18 GTPase activity is important for lipid droplet trafficking. Our results reveal a complex bi-directional cross-talk that takes place between LD-associated proteins and cytoskeletal elements that maintain lipid droplet dynamics in a highly organized manner. Our study provides a new insight in the regulation of LD dynamics and insulin signaling in adipocytes.
V. Puri: None. S. Banerjee: None. S. Jash: None.