Fat Storage-inducing Transmembrane Protein 2 Is Required for Normal Fat Storage in Adipose Tissue

Abstract

Background: FIT2 is an ER protein purported to be important for triglyceride lipid droplet formation. Results: FIT2 deficiency in adipose tissue results in lipodystrophy and metabolic dysfunction. Conclusion: FIT2 is required for normal triglyceride storage in adipose tissue. Significance: This study provides the first proof-of-principle mouse models indicating that FIT2 is essential for normal triglyceride storage in adipose tissue.

Mature lipid droplets are accessible to ER luminal proteins

“…FIT proteins constitute an evolutionary conserved class of ER proteins that bind triacylglycerol in vitro and they are important for neutral lipid storage in vivo (Gross et al, 2011;Kadereit et al, 2008). Deficiency of FIT2 in the adipose tissue of mice results in progressive lipodystrophy of white adipose depots and metabolic dysfunction (Miranda et al, 2014). In yeast, mouse fibroblasts and C. elegans, lack of FIT proteins results in budding of lipid droplets into the ER lumen (Choudhary et al, 2015).…”

Postnatal Deletion of Fat Storage-inducing Transmembrane Protein 2 (FIT2/FITM2) Causes Lethal Enteropathy

“…Mice-Mice carrying floxed FIT2 (L/L) alleles that were previously generated (11) Serum was collected via the retro-orbital vein. For EdU staining, mice were injected intraperitoneally with 160 g/g body weight of EdU (Molecular probes, Invitrogen) dissolved in PBS.…”

“…More recently, adipose tissue deficiency of FIT2 in mice was shown to lead to a progressive lipodystrophy associated with adipose tissue necrosis. At a cellular level, FIT2 deficiency in mouse primary adipocytes resulted in a significant reduction in LD number but an increase in LD size (11). Therefore, FIT2 plays a subtle but poorly understood role in LD biology, but it is essential for adipose tissue TG storage and survival.…”

“…We previously deleted FIT2 in an adipose tissue knock-out mouse model, leading to defects in LD storage of fat in white adipose tissue (WAT), infiltration of WAT with inflammatory macrophages, death of adipocytes, and metabolic dysfunction typical of lipodystrophies, which was significantly exacerbated by high fat feeding (11). As FIT2 is a ubiquitously expressed protein, we sought to understand its function in whole body metabolism by inducing whole body postnatal FIT2 deletion (iF2KO).…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…How seipin initiates droplet formation is still obscure, although it may serve as a scaffold for enzymes in the pathway of neutral lipid synthesis, such as the phosphatidate hydrolase lipin (Sim et al, 2012). FIT2, an ER protein that binds triacylglycerols, likely also contributes to droplet formation (Gross et al, 2011;Miranda et al, 2014). Cytoplasmic proteins such as PLIN3 (perilipin 3/Tip47), may facilitate membrane curvature that must accompany droplet formation (Skinner et al, 2009).…”