| abstract |
It has now been demonstrated that syndecan binds to and interacts with MC4-R, and thereby modulates neuropeptide regulation of body weight, via the agouti/MC4-R signaling pathway. Transgenic animals were made initially using a construct including a cytomegalovirus promoter and the 3' untranslated region, including the polyadenylation site, of the bovine growth hormone gene, as well as cDNA encoding syndecan-1. The mice express the syndecan-1 transgene in many tissues, with expression in the brain occurring preferentially in their hypothalamus. These mice are characterized by elevated levels of circulating syndecan-1 ectodomain and exhibit enormous weight gain after reaching sexual maturity, but have a relatively normal distribution of fat, are completely healthy and heterozygotes reproduce, and show other indicators associated with obesity in humans. Agouti mice which are transgenic for syndecan-1 ectodomain demonstrate that syndecan-1 and agouti interact, potentiating obesity. The double heterozygote shows both an earlier onset, and greater extent, of obesity than either normal agouti or the original transgenic syndecan-1 mice.Based on these studies and animal models, one can design and test compounds regulating obesity. These mice are also useful in understanding the factors involved in weight regulation and in designing and screening for drugs which are involved in weight regulation and that can either enhance or reduce appetite and activity. |