Life without white fat: a transgenic mouse

TLDR

The study introduces a transgenic mouse model to investigate the systemic effects of lifelong absence of white adipose tissue. By expressing a dominant‑negative A‑ZIP/F protein under the aP2 promoter, the mice block C/EBP and Jun transcription factor binding, abolishing white adipose tissue formation. These mice exhibit no white fat, reduced brown fat, hyperphagia, organomegaly, severe insulin resistance and hyperglycemia, and premature death, recapitulating features of human lipoatrophic diabetes.

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.