Abstract
Triglycerides within the cytosol of cells are stored in a phylogenetically conserved organelle called the lipid droplet (LD). LDs can be formed at the endoplasmic reticulum, but mechanisms that regulate the formation of LDs are incompletely understood. Adipose tissue has a high capacity to form lipid droplets and store triglycerides. Fat storage-inducing transmembrane protein 2 (FITM2/FIT2) is highly expressed in adipocytes, and data indicate that FIT2 has an important role in the formation of LDs in cells, but whether FIT2 has a physiological role in triglyceride storage in adipose tissue remains unproven. Here we show that adipose-specific deficiency of FIT2 (AF2KO) in mice results in progressive lipodystrophy of white adipose depots and metabolic dysfunction. In contrast, interscapular brown adipose tissue of AF2KO mice accumulated few but large LDs without changes in cellular triglyceride levels. High fat feeding of AF2KO mice or AF2KO mice on the genetically obese ob/ob background accelerated the onset of lipodystrophy. At the cellular level, primary adipocyte precursors of white and brown adipose tissue differentiated in vitro produced fewer but larger LDs without changes in total cellular triglyceride or triglyceride biosynthesis. These data support the conclusion that FIT2 plays an essential, physiological role in fat storage in vivo.
Highlights
FIT2 is an endoplasmic reticulum (ER) protein purported to be important for triglyceride lipid droplet formation
Differentiated Adipocyte Precursors from AF2KO Exhibited Fewer but Larger lipid droplet (LD)—To determine whether defects in LD formation could explain the lipodystrophic phenotype in AF2KO mice, we examined the cell-autonomous effects of FIT2 deficiency using preadipocytes from the stromal vascular cell fraction isolated from white adipose tissue (WAT) of AF2KO and L/L control mice
We show that FIT2 plays an important role in the storage of fat in white and brown adipose tissues
Summary
FIT2 is an ER protein purported to be important for triglyceride lipid droplet formation. Fat storage-inducing transmembrane protein 2 (FITM2/FIT2) is highly expressed in adipocytes, and data indicate that FIT2 has an important role in the formation of LDs in cells, but whether FIT2 has a physiological role in triglyceride storage in adipose tissue remains unproven. Primary adipocyte precursors of white and brown adipose tissue differentiated in vitro produced fewer but larger LDs without changes in total cellular triglyceride or triglyceride biosynthesis These data support the conclusion that FIT2 plays an essential, physiological role in fat storage in vivo. The enrichment of FIT2 in adipose tissue is probably related to the findings that both human and mouse FIT2 are direct targets of the adipogenic transcription factor PPAR␥, where they share a conserved intronic PPAR␥ response element [7,8,9] Taken together, these studies support an important role of FIT2 in LD accumulation. This study provides the first in vivo evidence that FIT2 is essential for normal fat storage
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