Like many complex physiological conditions, obesity results from the interaction of multiple genes and environmental factors. In a large case-control study of nuclear families in France, Philippe Froguel and colleagues used genome-wide scans of a chromosomal region linked with susceptibility to hone in on a new candidate gene for obesity. The same group had previously found strong linkage between a region of chromosome 10 and obesity. GAD2, one of the genes in the region, codes for an enzyme that catalyzes the production of a neurotransmitter in the hypothalamus that stimulates appetite, and is therefore an interesting candidate.

Screening genomic data on 575 obese subjects and 646 controls for different GAD2 alleles, Froguel and colleagues identified one group of alleles as "protective" against obesity and another as increasing risk. These findings were supported by genetic screens of the nuclear families participating in the study. And when the researchers investigated the physiological effect of the "highest risk" GAD2 variant in a mouse cell line, they found it caused a 6-fold increase in GAD2 transcript levels compared to the "wild-type" cells without the variant.

The researchers hypothesize that an overexpression of the GAD2 gene may increase the amount of the neurotransmitter GABA in the hypothalamus, thereby increasing GABA's orexigenic effects and leading to overeating. Studies in turkeys injected with muscimol, a GABA activator, and mice overexpressing a protein that regulates GABA localization support this notion; the more musimol the turkeys received, the more they ate, while the mice gained more weight and showed higher fat deposits.

Taken together, these results strongly suggest that genetic variations in GAD2 influence the risk for obesity. The researchers hope their work will inspire others to replicate their results, to confirm the genetic link and to elucidate the underlying biology of body weight control and eating behav
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Contact: Barbara Cohen
bcohen@plos.org
415-624-1206
Public Library of Science
3-Nov-2003

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