MCH ACTION AS DEFINED THROUGH GENE KNOCKOUT

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Obesity is a serious medical condition with complex etiology; it is a significant risk factor for a number of illnesses including type II diabetes, coronary artery disease a number of neoplasms including endometrial and colon cancer. Although very common, the causes of obesity are poorly understood and available treatments are not particularly effective. A number of peripheral hormones and neuropeptides have been implicated in the pathogenesis of the impaired energy balance which results in obesity. We discovered that the hypothalamic peptide, melanin concentrating hormone is important in the regulation of energy balance. In addition to a number of physiologic studies we generated a mouse in which the MCH gene was ablated. Homozygous MCH-/- mice have a lean phenotype, with a 25% reduction in total body weight and 50% reduction in total body fat and reduced levels of leptin. Decreased eating during the dark cycle contributes t least in part to the phenotype, however, the reduction in eating is only 15%. Preliminary data indicates that ablation of the MCH gene may also lead to increased oxygen consumption. This study proposes to examine the causes of the lean phenotype in detail and to ascertain the relative contributions of MCH and the two other peptides derived from the MCH gene, N-EI and N- GE. To determine the role of MCH in mediating the orexigenic or appetite inhibiting actions of other neuropeptides (NPY, alphaMSH, GLP-1) the effect of a number of appetite regulating peptides in MCH-/- mice will be assessed. In addition to examine the importance of MCH in mediating obesity in single gene models of rodent obesity MCH-/- mice will be crossbred to leptin deficient (ob/ob) mice and leptin resistance A/gamma (agouti) mice. MCH-/- mice will also be crossbred to mice with ablations in NPY or orexin, other neuropeptides implicated in energy, balance, to determine the effect of multiple gene ablation on energy balance.