Life without white fat: a transgenic mouse
- Jaideep Moitra1,7,
- Mark M. Mason2,7,
- Michelle Olive1,
- Dmitry Krylov1,
- Oksana Gavrilova2,
- Bernice Marcus-Samuels2,
- Lionel Feigenbaum5,
- Eric Lee3,
- Toshifumi Aoyama6,
- Michael Eckhaus4,
- Marc L. Reitman2,8, and
- Charles Vinson1,8
- 1Laboratory of Biochemistry, National Cancer Institute (NCI); 2Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases; 3Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development; 4Veterinary Resources Program, Office of Research Services, National Institutes of Health (NIH), Bethesda, Maryland 20892 USA; 5Science Application International Corp., Frederick, NCI–Frederick Cancer Research and Development Center, Frederick, Maryland 21702 USA; 6Department of Biochemistry, Shinshu University School of Medicine, Matsumoto 390, Japan
Abstract
We have generated a transgenic mouse with no white fat tissue throughout life. These mice express a dominant-negative protein, termed A-ZIP/F, under the control of the adipose-specific aP2 enhancer/promoter. This protein prevents the DNA binding of B-ZIP transcription factors of both the C/EBP and Jun families. The transgenic mice (named A-ZIP/F-1) have no white adipose tissue and dramatically reduced amounts of brown adipose tissue, which is inactive. They are initially growth delayed, but by week 12, surpass their littermates in weight. The mice eat, drink, 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, with reduced leptin (20-fold) and elevated serum glucose (3-fold), insulin (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 human disease lipoatrophic diabetes (Seip-Berardinelli syndrome), indicating that the lack of fat can cause diabetes. The myriad of consequences of having no fat throughout development can be addressed with this model.
