LIFE WITHOUT WHITE FAT - A TRANSGENIC MOUSE

We have generated a transgenic mouse with no white fat tissue througho ut life. These mice express a dominant-negative protein, termed A-ZIP/ F, under the control of the adipose-specific aP2 enhancer/promoter. Th is protein prevents the DNA binding of B-ZIP transcription factors of both the C/EBP and Tun families. The transgenic mice (named A-ZIP/F-1) have no white adipose tissue and dramatically reduced amounts of brow n adipose tissue, which is inactive. They are initially growth delayed , but by week 12, surpass their littermates in weight. The mice eat, d rink, and urinate copiously, have decreased fecundity, premature death , and frequently die after anesthesia. The physiological consequences of having no white fat tissue are profound. The liver is engorged with lipid, and the internal organs are enlarged. The mice are diabetic, w ith reduced leptin (20-fold) and elevated serum glucose (3-fold), insu lin (50- to 400-fold), free fatty acids (2-fold), and triglycerides (3 - to 5-fold). The A-ZIP/F-1 phenotype suggests a mouse model for the h uman disease lipoatrophic diabetes (Seip-Berardinelli syndrome), indic ating that the lack of fat can cause diabetes. The myriad of consequen ces of having no fat throughout development can be addressed with this model.