application): It is proposed in this application to test whether the DNA binding protein HMGI-C is involved in the development of obesity in the ob/ob mouse. This will be accomplished by breeding ob/ob mice in which one or both HMGI-C alleles have been disrupted, and assessing the impact of these changes on the development of the obese phenotype and its associated abnormalities. The expected result of decreased obesity will provide support for targeting the HMGI-C gene/protein for anti-obesity drug development. Targeted disruption of the HMGI-C gene has been shown by Dr. Chada to result in the pigmy (pg/pg) mouse, which was initially described as a spontaneous mutant with a 20-fold decrease in body fat. This, and the subsequent observations by Dr. Chada's group that mutations of HMGI-C and HMGI-(Y) are found in human lipomas provide the rationale for the proposed studies. Preliminary data is presented that expression of the HMGI-C and HMGI-(Y) genes are elevated in both ob/ob and db/db mice, and that HMGI-C+/- ob/ob mice (N = 2) have delayed weight gain compared to HMGI-C +/+ ob/ob controls. The ob/ob phenotype is considered to be a good model of human obesity that is due to hyperphagia, so that effects of the absence of HMGI-C in mice may have relevance to human obesity.
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