MCH ACTION AS DEFINED THROUGH GENE KNOCKOUT

肥胖是一种病因复杂的严重疾病；它是许多疾病的重要危险因素，包括II型糖尿病，冠状动脉疾病和一些肿瘤，包括子宫内膜和结肠癌。虽然肥胖很常见，但人们对肥胖的原因知之甚少，现有的治疗方法也不是特别有效。许多外周激素和神经肽与导致肥胖的能量平衡受损的发病机制有关。我们发现下丘脑肽、黑色素浓缩激素在调节能量平衡中起重要作用。除了一些生理学研究外，我们还产生了一只小鼠，其中MCH基因被切除。纯合子MCH-/-小鼠具有瘦表型，总体重减少25%，总脂肪减少50%，瘦素水平降低。在黑暗周期期间减少饮食对这种表型的贡献最小，然而，减少的饮食只占15%。初步数据表明，MCH基因的消融也可能导致耗氧量增加。本研究旨在详细研究精益表型的原因，并确定MCH和来自MCH基因的另外两种肽N- ei和N- GE的相对贡献。为了确定MCH在介导其他神经肽（NPY, alpha - sh, GLP-1）的增氧或食欲抑制作用中的作用，我们将评估MCH-/-小鼠中一些食欲调节肽的作用。除了在啮齿动物肥胖单基因模型中检测MCH介导肥胖的重要性外，MCH-/-小鼠将与瘦素缺乏（ob/ob）小鼠和瘦素抵抗A/ γ (agouti)小鼠杂交。MCH-/-小鼠也将与NPY或orexin（其他与能量平衡有关的神经肽）消融的小鼠杂交，以确定多基因消融对能量平衡的影响。

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.