Regulatory Responses to Positive Energy Balance

对正能量平衡的监管反应

基本信息

批准号：
6477838
负责人：
RANDY J SEELEY
金额：
$ 29.68万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-30 至 2007-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The incidence of obesity has reached epidemic proportions, is a major health burden, and costs the U.S. billions of dollars in health care and lost productivity. Failure to develop effective treatments for obesity is in large part due to a lack of clear understanding as to how food intake and energy balance are regulated by the CNS. Thus, research to determine the processes by which food intake and energy balance are controlled is likely to have a major impact on public health, but the research to date has been imbalanced. For whereas considerable effort has been devoted to understanding the neurochemical response to negative energy balance, relatively little attention has been devoted to the inverse situation of positive energy balance. This oversight is significant since obesity is necessarily associated with periods of positive energy balance and therefore can be considered as a failure of the body weight regulatory system to respond appropriately to positive energy balance. Thus studying the responses to positive energy balance may provide valuable clues concerning the etiology of obesity. Moreover, the regulatory responses to positive energy balance represent the recruitment of endogenous systems that produce reduced food intake, increased energy expenditure and significant weight loss. Finding potential ways to mimic or trigger these endogenous regulatory response systems could provide unique insights and therapeutic strategies for the treatment of obesity. The current proposal seeks to identify critical aspects of this response system. When animals are force-fed calories in excess of caloric need (involuntary overfeeding), their spontaneous food intake drops to near zero and they gain body weight. Additionally, for some time after the overfeeding regimen is terminated, spontaneous food intake remains low until body weight has returned to control levels. Our data indicate that this regulatory response to positive energy balance is mediated by the CNS melanocortin system. We propose assessing several hypotheses concerning how the CNS melanocortin system orchestrates the response to positive energy balance. First, we will determine the critical population of melanocortin receptors that mediate the reduced food intake and increased energy expenditure that follow a period of positive energy balance. Second, we will determine the critical inputs into the melanocortin system that signal positive energy balance. Finally, we will evaluate the unique effects of an endogenous melanocortin receptor antagonist that counteracts the normal response to positive energy balance. The information from this proposal will be critical to a complete picture of how energy balance is regulated and how disorders of energy balance such as obesity may be treated.

描述（申请人提供）：肥胖发生率已达到流行病的比例，是一个重大的健康负担，给美国造成了数十亿美元的损失医疗保健费用和生产力损失。未能有效开发肥胖的治疗在很大程度上是由于缺乏明确的认识中枢神经系统如何调节食物摄入和能量平衡。因此，研究确定食物摄入和能量平衡的过程受控可能会对公共健康产生重大影响，但研究迄今为止，一直是不平衡的。尽管已经付出了相当大的努力了解对负能量平衡的神经化学反应，对于相反的情况，人们的关注相对较少正能量平衡。这种监督很重要，因为肥胖是必然与正能量平衡时期相关，因此可以被认为是体重调节系统未能做出反应适当地达到正能量平衡。因此研究了对正能量平衡可能提供有关病因学的有价值的线索肥胖。此外，对正能量平衡的监管反应代表减少食物生产的内源系统的补充摄入量增加，能量消耗增加，体重显着减轻。寻找模仿或触发这些内源性调节反应系统的潜在方法可以为治疗提供独特的见解和治疗策略肥胖。当前的提案旨在确定这一问题的关键方面响应系统。当动物被强制喂食超过热量需求的热量时（非自愿的过度喂养），他们的自发食物摄入量下降到接近于零，并且他们获得了体重。此外，在过度喂养后的一段时间内终止后，自发食物摄入量仍然较低，直到体重恢复来控制水平。我们的数据表明，这种监管反应是积极的能量平衡由中枢神经系统黑皮质素系统介导。我们建议评估关于中枢神经系统黑皮质素系统如何协调的几种假设对正能量平衡的反应。首先，我们将确定关键介导食物摄入减少的黑皮质素受体群体经过一段时间的正能量平衡后，能量消耗增加。其次，我们将确定黑皮质素系统的关键输入发出正能量平衡的信号。最后，我们将评估独特的效果一种内源性黑皮质素受体拮抗剂，可抵消正常的黑皮质素受体拮抗剂对正能量平衡的反应。该提案的信息将是对于全面了解能量平衡如何调节以及如何调节至关重要能量平衡紊乱例如肥胖可以得到治疗。