The cloning and sequencing of the mouse and the human obesity (OB) genes have been greeted with enormous excitement. When mice have a defective OB gene on both chromosomes, they are very obese and treatment with leptin, the product of the OB gene, causes rapid weight loss. This led to the hope that obese humans also had a defective OB gene, and treatment with leptin would also cause weight loss. However, many subsequent studies have shown that obese humans have too much leptin, not too little, and no mutations of the OB gene itself were found. Thus, the OB gene - leptin story is far more complex than originally thought.
In 1993 DE Comings and colleagues found that variants of the dopamine D2 receptor gene (DRD2), originally reported by K Blum and EP Noble as being associated with severe alcoholism, were also associated with obesity. Blum and Noble confirmed this association, and both groups found an association between the DRD2 gene and drug addiction. All three of these substances (alcohol, drugs and food), stimulate the reward pathways of the brain. Now Comings and coworkers found that the OB and DRD2 genes were additive in their effect on obesity in young women. Both genes combined accounted for 22% of the obesity in young women.
These results are consistent with obesity being the result of many different genes (polygenic), with a greater involvement of genetic factors in women and younger subjects, and suggest that variants of the OB gene are causally involved not only with human obesity but with its associated behavioral disorders. An independent commentary by Dr. Gerald J. LaHoste (University of California at Irvine, USA; FAX: + 1 714 824-2447; phone: +1 714 824-4722; e-mail: email@example.com) also appears in the current issue of Molecular Psychiatry.
Authors: DE Comings, R Gade, J MacMurray, D Muhleman, P Johnson, R Verde, WR
Peters. City of Hope National Medical Center, Duarte, California, USA and Loma
Linda University, Loma Linda, California, USA
Molecular Psychiatry 1996; vol. 1, issue 4 (September 1996).
***For information on the scientific aspects of the article please contact the author: Dr. David E. Comings, Department of Medical Genetics,
City of Hope National Medical Center,
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phone: +1 (818) 359-8111; FAX: +1 (818) 301-8980
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