Storage of energy as triglyceride in large adipose-specific lipid droplets is a 
fundamental need in all mammals. Efficient sequestration of fat in adipocytes 
also prevents fatty acid overload in skeletal muscle and liver, which can impair 
insulin signaling. Here we report that the Cide domain-containing protein Cidea, 
previously thought to be a mitochondrial protein, colocalizes around lipid 
droplets with perilipin, a regulator of lipolysis. Cidea-GFP greatly enhances 
lipid droplet size when ectopically expressed in preadipocytes or COS cells. 
These results explain previous findings showing that depletion of Cidea with 
RNAi markedly elevates lipolysis in human adipocytes. Like perilipin, Cidea and 
the related lipid droplet protein Cidec/FSP27 are controlled by peroxisome 
proliferator-activated receptor gamma (PPARgamma). Treatment of lean or obese 
mice with the PPARgamma agonist rosiglitazone markedly up-regulates Cidea 
expression in white adipose tissue (WAT), increasing lipid deposition. 
Strikingly, in both omental and s.c. WAT from BMI-matched obese humans, 
expression of Cidea, Cidec/FSP27, and perilipin correlates positively with 
insulin sensitivity (HOMA-IR index). Thus, Cidea and other lipid droplet 
proteins define a novel, highly regulated pathway of triglyceride deposition in 
human WAT. The data support a model whereby failure of this pathway results in 
ectopic lipid accumulation, insulin resistance, and its associated comorbidities 
in humans.