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.
University of Minnesota Ph.D. dissertation. September 2009. Major: Biochemistry, Molecular Bio, and Biophysics. Advisor: Michel M. Sanders. 1 computer file (PDF); xii, 213 pages.
Saykally, Jessica Nicole.
Identification of the transcription factor ZEB1 as a novel modulator of adiposity..
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