The role of opioid peptides in eating behaviours and obesity

在过去的二十年里，许多人口统计报告描述了世界范围内肥胖和超重人口比例的增加，因此，与肥胖相关的健康问题急剧增加。这个问题仍然在增加，尽管许多超重的人试图控制他们的饮食，考虑到不利的健康后果，也因为大多数人认为一个精益和健康的身体是更可取的。许多研究人员注意到不受控制的食物摄入和药物成瘾之间的共同点，包括特定的行为，神经元回路和神经递质系统。最重要的是，在一些肥胖者中观察到的饮食行为失控和强迫性进食与患有药物依赖的人的强迫性吸毒行为相似。已经描述了几种神经递质和神经调节系统，它们在这些过程中起关键作用，例如多巴胺能系统、内源性大麻素系统或阿片系统。这项建议的重点是内源性阿片系统，这是一个关键的调节享乐反应。阿片肽参与食物偏好和进食行为的执行控制在一些研究中显示，但这些观察结果背后的确切机制仍在讨论中。因此，人类和动物的研究表明，冲动与阿片类药物成瘾有关，但尚不完全清楚这是成瘾过程的原因还是结果。同样，执行控制功能障碍也与饮食失调有关，如厌食症和神经性贪食症，以及肥胖症。在以前的研究中，我们研究了阿片肽在动物行为调节中的功能。我们产生的小鼠缺乏阿片肽脑啡肽和强啡肽表明，这些肽对药物奖励和成瘾，情绪，应激反应和伤害感受有深远的影响。该建议的主要假设是，长期自愿食用高热量可口食物，导致肥胖，产生阿片信号的改变。这些变化反过来影响享乐方面和食物摄入的执行控制。为了验证这一假设，我们将在具有遗传破坏的阿片信号传导的动物中使用行为和分子研究的组合。我们的目的是阐明内源性阿片系统的特定成分在调节瘦和肥胖受试者的食物摄入中的作用。一个特别的重点将放在肥胖引起的变化的食物奖励和执行控制功能的激励显着性。

Numerous demographic reports over the last two decades described a worldwide increase in the percentage of obese and overweight people and, consequently, a tremendous rise of obesity-related health problems. The problem is still increasing, even though many overweight individuals attempt to control their diet in view of the adverse health consequences and also because most people consider a lean and fit body to be more desirable. Many investigators have noted commonalities between an uncontrolled intake of food and drug addiction, including specific behaviours, neuronal circuits and neurotransmitter systems. Most importantly, the loss of control over eating behaviours and a compulsive food intake observed in some obese individuals bears a resemblance to compulsive drug taking behaviours in people suffering from drug dependence. Several neurotransmitter and neuromodulatory systems have been described that are critically involved in these processes, such as the dopaminergic system, the endocannabinoid system, or the opioid system. The focus of this proposal is on the endogenous opioid system, which is a critical regulator of hedonic responses. The involvement of the opioid peptides in food preference and in the executive control of eating behaviour was shown in some studies, but the exact mechanisms underlying these observations are still discussed. Thus, human and animal studies for example revealed that impulsivity is associated with opiate addiction, but it is not entirely clear if this is cause or consequence of the addiction process. Similarly, executive control dysfunctions have also been implicated in eating disorders, such as anorexia and bulimia nervosa, as well as obesity. In previous studies we investigated the function of opioid peptides in the modulation of animal behaviours. We generated mice deficient for the opioid peptides enkephalin and dynorphin showed that these peptides have a profound effect on drug reward and addiction, emotionality, stress-responses and nociception. The main hypothesis of this proposal is that a prolonged voluntary consumption of high caloric palatable food, leading to obesity, produces alterations in opioid signalling. These alterations in turn impact on hedonic aspects and executive control of food intake. To test this hypothesis we will use a combination of behavioural and molecular studies in animals with genetically disrupted opioid signalling. We aim to clarify the role of specific components of the endogenous opioid system in the regulation of food intake in lean and obese subjects. A particular emphasis will be placed on obesity-induced changes in the incentive salience of food rewards and executive control functions.