White adipose tissue (WAT) functions as an energy reservoir where excess 
circulating fatty acids are transported to WAT, converted to triglycerides, and 
stored as unilocular lipid droplets. Fat-specific protein 27 (FSP27, CIDEC in 
humans) is a lipid-coating protein highly expressed in mature white adipocytes 
that contributes to unilocular lipid droplet formation. However, the influence 
of FSP27 in adipose tissue on whole-body energy homeostasis remains unclear. 
Mice with adipocyte-specific disruption of the Fsp27 gene (Fsp27(ΔAd)) were 
generated using an aP2-Cre transgene with the Cre/LoxP system. Upon high-fat 
diet feeding, Fsp27(ΔAd) mice were resistant to weight gain. In the small WAT of 
these mice, small adipocytes containing multilocular lipid droplets were 
dispersed. The expression levels of the genes associated with mitochondrial 
abundance and brown adipocyte identity were increased, and basal lipolytic 
activities were significantly augmented in adipocytes isolated from Fsp27(ΔAd) 
mice compared with the Fsp27(F/F) counterparts. The impaired fat-storing 
function in Fsp27(ΔAd) adipocytes and the resultant lipid overflow from WAT led 
to marked hepatosteatosis, dyslipidemia, and systemic insulin resistance in 
high-fat diet-treated Fsp27(ΔAd) mice. These results demonstrate a critical role 
for FSP27 in the storage of excess fat in WAT with minimizing ectopic fat 
accumulation that causes insulin-resistant diabetes and non-alcoholic fatty 
liver disease. This mouse model may be useful for understanding the significance 
of fat-storing properties of white adipocytes and the role of local FSP27 in 
whole-body metabolism and estimating the pathogenesis of human partial 
lipodystrophy caused by CIDEC mutations.