Dopamine mechanisms in development of type-2 diabetes

描述(申请人提供)：肥胖导致或加重许多慢性疾病，最显著的是非胰岛素依赖型糖尿病(NIDDM)。大多数肥胖是由适度但长期的过量饮食引起的。缺乏CCK-A受体的大冢长万德岛肥胖(OLETF)大鼠会出现过度吞噬、肥胖，并逐渐发展为NIDDM。在OLETF大鼠中，增加食物摄入量对于肥胖的发生是必要的，这表明NIDDM继发于糖尿病前期的吞噬功能亢进。因此，OLETF大鼠是人类最常见的NIDDM模型。这种菌株慢性吞噬功能亢进的根本原因尚不清楚，也不能完全用他们的外周饱腹感缺陷来解释。相反，对控制进食量至关重要的中央通路功能障碍是最有可能的因素。本课题以OLETF大鼠为研究对象，研究2型糖尿病发生发展过程中中枢兴奋系统中多巴胺(DA)信号与高吞噬行为表型的关系。我们认为，中隔区多巴胺(DA)系统中多巴胺能功能的改变通过增加对通常首选食物的嗅觉刺激效应的偏好，导致OLETF大鼠暴饮暴食。 行为、神经化学和组织学方法将被用来挑战这一假说。该应用有四个特定的目的：1)表征三个年龄的OLETF大鼠的基本多巴胺能表型(基础和刺激的DA释放和再摄取)，反映糖尿病的发展；2)通过研究糖尿病前期OLETF大鼠的口感和吸收后的营养偏好功能来表征高摄食行为表型；3)通过比较糖尿病前期OLETF大鼠和年龄和体重匹配的非突变对照(LETO)大鼠假喂养首选蔗糖或脂肪溶液的效果，评估行为与DA信号的关系；4)通过使用精神刺激剂哌醋甲酯的慢性治疗来逆转OLETF大鼠对蔗糖和脂肪的偏好和摄入，并延缓糖尿病的发生，以解决这种关系的因果关系。这些研究将有助于确定多巴胺能系统的可塑性如何影响与过度吞噬和饮食诱导的NIDDM的发展相关的行为和代谢因素。

DESCRIPTION (provided by applicant): Obesity causes or exacerbates many chronic illnesses, most notably non-insulin-dependent diabetes mellitus (NIDDM). Most obesity is caused by modest, but chronic overeating. Otsuka Long-vans Tokushima fatty (OLETF) rats, which lack the CCK-A receptor, are hyperphagic, obese, and gradually develop NIDDM. In OLETF rats, increased food intake is necessary for the development of obesity, suggesting that the NIDDM is secondary to the prediabetic hyperphagia. Thus, OLETF rats are reasonable model of the most prevalent form of NIDDM in humans. The underlying cause of the chronic hyperphagia in this strain is unknown and cannot be explained entirely by their peripheral satiation deficits. Rather, a dysfunction in central pathways critical to the control of meal size is the most likely contributor. In this project, OLETF rats are used to study the relationship between the hyperphagic behavioral phenotype and dopamine (DA) signaling within the central motivational system during the development of type-2 diabetes. We propose that altered dopaminergic functioning in the mesoaccumbens dopamine (DA) system contributes to the overeating in OLETF rats by increasing preference for the orosensory stimulatory effects of normally preferred foods. Behavioral, neurochemical and histological methods will be employed to challenge this hypothesis. The application has four specific aims: 1) to characterize the basic dopaminergic phenotype (basal and stimulated DA release and reuptake) of the OLETF rats at three ages, reflecting the development of diabetes; 2) to characterize hyperphagic behavioral phenotype by investigating nutrient preference functions in prediabetic OLETF rats based on their orosensory and postabsorbtive properties; 3) to assess the relationship between behavior and DA signaling by comparing the effects of sham-feeding of preferred sucrose or fat solutions between prediabetic OLETF and age- and body weight-matched non-mutant control (LETO) rats; 4) to address causality of the relationship by using chronic treatment of the psychostimulant methylphenidate to reverse preference for and intake of sucrose and fat, and to delay onset of diabetes in OLETF rats. These studies will help determine how plasticity in the dopaminergic system affects behavioral and metabolic factors related to hyperphagia and the development of dietary-induced NIDDM.