Obesity is a multifactorial disorder that is a significant risk factor for Type II diabetes, hypertension, and coronary heart disease. Although single genetic loci are frequently associated with obesity in mice, human obesity is rarely defined by a single gene disorder. Instead, numerous loci are correlated with a predisposition to obesity in humans. Interestingly, four genome-wide scans for human genes associated with early onset obesity from different research groups and using different populations have revealed a major susceptibility locus on chromosome 10 in the vicinity of the TCF8 gene (1 0p11-12). TCF8 encodes an estrogen-inducible transcription factor known as ZEB1 or EF1, which can activate or repress genes depending on the DNA context. ZEB1 is expressed in low levels in most tissues, especially all tissues of mesodermal origin, but can be induced about 7-fold at the transcriptional level and 10- to 15-fold at the protein level by estrogen. The biological role of ZEB1 remains under investigation, but it appears to be important in the development of mesenchymal tissues, such as adipose tissue, and in the conversion of some types of cancer from a localized to invasive phenotype.
We hypothesize that mutations in or near TCF8 result in a gain or loss of function of ZEB1, making those individuals susceptible to childhood or adolescent obesity. Furthermore, because TCF8 is induced by estrogen, we propose that in the adult, pre-menopausal female that estrogen induces ZEB1, and this is protective against obesity. One goal of this proposal is to investigate whether ZEB1 plays a role in adipogenesis using cell culture models of adipogenesis and diet-induced obese wild type and TCF8 knockout mice, treated with or without estrogen. The other major goal is to determine whether individuals with early onset obesity associated with the 10p11-12 locus have a mutation(s) in TCF8.
The data from these experiments are likely to contribute significantly to our understanding of the basis of childhood and adolescent obesity and to help address the role that estrogen might play in preventing obesity in women.
ZEB1 and the Development of Obesity
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