Transgenic expression of viral transcription factors leads to metabolic syndrome in mice.

摘要

Metabolic syndrome is a huge public health problem and recent evidence suggests that elevated glucocorticoid action in tissues plays a major role in its etiology. An enzyme designated 11 beta-hydroxysteroid dehydrogenase type 1 (HSD-1) converts inactive cortisone to active cortisol. To study the kinetics of HSD-1 expression and its association with the development of this disease, I generated conditional transgenic mice, with the goal of regulating HSD-1 expression in the adipose by treating the mice with doxycycline. To accomplish this, I generated three constructs: Transgenes containing the reverse tetracycline transcription activator (rtTA) (which contains the herpes virus VP16 activation domain), and the tetracycline transcription silencer (tTS) were both placed under control of the adipose-specific aP2 promoter, and the human HSD-1 cDNA was placed under the control of the tetracycline operator/CMVie promoter. Genotyping of resulting mice confirmed the presence of all three constructs in three distinct mouse lines. Although the conditional expression of HSD-1 was not achieved, these transgenic mice exhibited sequelae of metabolic syndrome, including increased body weight and fat re-distribution with increased visceral fat but decreased peripheral fat. The transgenic mice also developed hyperinsulinemia, hypercholesterolemia, and liver dysfunction with elevated liver weight, liver enzymes, and hepatic steatosis. Furthermore, leukocyte cell counts and monocyte chemotactic protein-1 (MCP-1) levels were increased, suggesting a proinflammatory state of the transgenic mice. Surprisingly, a double transgenic mouse line that contained only the transcriptional regulator elements, rtTA and tTS, exhibited a metabolic syndrome phenotype virtually indistinguishable from that observed with the other lines containing all three transgenes. Gene expression profiling revealed changes that were consistent with the observed phenotype. The rtTA and tTS DNAs were transfected individually into adipocytic 3T3-L1 cells and only the rtTA element resulted in gene expression changes analogous to those observed in the transgenic mice. These studies support the conclusion that the viral VP16 element (present within rtTA) is driving the development of metabolic syndrome in these mice. Since viral transcription factors can regulate expression of host genes, I propose that activation of the host genome by viral proteins can affect specific pathways leading to metabolic disorders in humans.