Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is an autosomal recessive disorder characterized by an almost complete loss of adipose tissue, insulin resistance and fatty liver. Here, we create the first murine model of BSCL2 by targeted disruption of seipin, the causative gene for BSCL2. Compared with their wild-type littermates, the seipin(-/-) mice are viable and of normal weight but display significantly reduced adipose tissue mass, hepatic steatosis, glucose intolerance and hyperinsulinemia. The levels of leptin and adiponectin were both significantly decreased in seipin(-/-) mice, so were non-esterified fatty acids upon fasting. Surprisingly, however, hypertriglyceridemia which is common in human BSCL, was not observed in seipin(-/-) mice. Our findings suggest a possible tissue-autonomous role of seipin in liver lipid storage. The availability of the seipin(-/-) mice should help elucidate the molecular function of seipin and lead to a better understanding of the many metabolic consequences of human BSCL2.