Identification of the transcription factor ZEB1 as a novel modulator of adiposity.

Abstract

Obesity and its subsequent metabolic disorders have become global health problems. While this is largely due to environmental influences, the propensity to gain weight also has a significant genetic component. In an effort to identify genes that contribute to obesity, several genome-wide scans on obese patient populations have been performed. One consistent location that displayed linkage to obesity is chromosome 10p11-12. A likely candidate gene within this region is the TCF8 gene, which encodes the ZEB1 transcription factor. To test whether TCF8 is an anti-obesity gene, DNA from obese patients was genotyped using single nucleotide polymorphisms throughout the TCF8 genetic locus. Logarithm of the odds for linkage of TCF8 to childhood obesity was high in two regions. Sequencing of a subset of the patient DNAs revealed a polymorphism that results in an amino acid change within the coding region of 50% of the patients. More tests will be required to determine whether the polymorphism has a functional consequence. In addition, TCF8+/- and wild type (WT) C57BL/6 mice were fed a high fat diet or regular chow diet for 20 weeks and their body weights, body composition, and metabolic parameters measured. TCF8 +/- female mice were significantly heavier on both diets due to an increase in fat. Increased adipose mass was the result of increased adipocyte size and was sufficient to cause metabolic consequences. Interestingly, this phenotype was not observed in male or female mice treated with the specific anti-estrogen Faslodex, suggesting that ZEB1 is mediating some of estrogen’s anti-obesity effects. Expression of several known estrogen-regulated genes important in lipolysis and lipogenesis measured in TCF8 +/- and WT suggests that ZEB1 modulates the flux of lipids in adipocytes. This thesis identifies TCF8 as an anti-obesity gene in mice and potentially in humans. Loss of one copy of the TCF8 gene is sufficient to increase adiposity and subsequent metabolic consequences. This is a novel observation as no one has previously proposed a role for ZEB1 in adipose tissue. In addition, this data contributes to our understanding of sexual dimorphism in metabolism.