MCH AND THE INTEGRATION OF ENERGY BALANCE

在美国，肥胖已经成为一个严重的健康问题。一旦确定肥胖 几乎没有有效的治疗方法。越来越明显的是，除了过量的食物摄入， 在啮齿类动物和哺乳动物中，能量消耗是肥胖发展的重要因素， 人类能量消耗有几个组成部分，包括静息能量消耗和运动活动（动机行为）期间消耗的能量。现在认识到，在摄食中起作用的肽也调节能量消耗。因此，增加食欲的肽然后减少能量消耗，而那些抑制食欲的肽往往增加能量消耗。黑色素浓集激素（MCH）最初被确定为刺激食欲的神经肽。它也已成为能量消耗的关键调节因子，可能通过调节交感神经活动对静息能量消耗产生影响，以及最可能通过影响多巴胺能信号传导对与运动活动相关的能量消耗产生影响。我们已经开发了一种缺乏MCH基因的小鼠模型（MCH-KO或MCH-/-），并将动物回交10代到同质遗传背景C57 BL/6上。缺乏MCH的小鼠是瘦的。在一个混合的背景下，瘦导致减少喂养和增加能量消耗的组合。在BL/6背景下，瘦型是次要的能量消耗增加。在普通饮食中，静息能量消耗增加，运动活动没有变化。缺乏MCH的小鼠抵抗饮食诱导的肥胖;当置于HF饮食中时，MCH-KO显示出静息能量消耗的额外增加以及运动活性的增加。这项研究的目的是利用这种缺乏MCH的小鼠模型来研究MCH在调节交感神经活动和多巴胺能信号传导中的作用。

Obesity has become a serious health problem in the United States. Once obesity is established there is little effective treatment. It is increasingly apparent that in addition to excess food intake, energy expenditure is an important contributor to the development of obesity, both in rodents and humans. Energy expenditure has several components including resting energy expenditure and the energy spent during locomotor activity (motivated behavior). It is now recognized that peptides that play are role in feeding also regulate energy expenditure. Thus peptides that increase appetite then to decrease energy expenditure while those that inhibit appetite tend to increase energy expenditure. Melanin-concentrating hormone (MCH) was initially identified as a neuropeptide that stimulates appetite. It has also emerged as a key regulator of energy expenditure and has effects both on resting energy expenditure, probably through modulation of sympathetic activity, as well as energy expenditure associated with locomotor activity, most likely through influences on dopaminergic signaling. We have developed a mouse model lacking the gene for MCH (MCH-KO or MCH-/-) and backcrossed the animals for 10 generations onto a homogeneous genetic background, C57BL/6. Mice lacking MCH are lean. On a mixed background leanness resulted from a combination of decreased feeding and increased energy expenditure. On the BL/6 background the lean phenotype is secondary to increased energy expenditure. On a chow diet, resting energy expenditure is increased and there is no change in locomotor activity. Mice lacking MCH resist diet induced obesity; when placed on a HF diet MCH-KO demonstrate and additional increase in resting energy expenditure as well as increased locomotor activity. The aims of this grant are to use this mouse model which lacks MCH to examine the role of MCH in modulate sympathetic activity and dopaminergic signaling.