Hypothalamic neurotransmitter systems & eating behavior

描述(申请人提供)：膳食脂肪会导致暴饮暴食和肥胖。我们最近的研究表明，摄入脂肪和由此导致的循环脂类增加刺激了下丘脑肽，甘丙肽。反过来，较高的甘丙肽进一步增加食物的摄入量，特别是高脂肪饮食。这些发现导致了一个新的建议，即存在一个正反馈回路，涉及膳食脂肪、循环中的甘油三酯(TG)和下丘脑多肽，它们以非稳态的方式促进富含脂肪的食物的过量摄入。这一正向循环先发制人并延迟了正常情况下限制食物摄入量的稳态负反馈信号的有效开始。初步研究表明，阿片肽脑啡肽和强啡肽也可能参与了这一过程，其作用方式与甘丙肽非常相似。此外，这些下丘脑肽可能与伏隔核中的多巴胺(DA)有关，后者被认为可以增强进食动机。这一新的证据使我们提出了以下六个具体目标，旨在测试下丘脑肽系统、伏隔核DA和脂类在促进高脂肪饮食过量饮食中的具体作用。我们计划：1)用急性实验范式在大鼠中更准确地测试循环脂类参与众所周知的饮食脂肪对总热量摄取的刺激作用；2)确定饮食脂肪和内源性TG对特定下丘脑多肽的影响；3)研究伏隔DA在下丘脑多肽和饮食脂肪对热量摄取影响中的作用；4)确定神经底物并确定它们在脂肪诱导的吞噬现象中的本质；5)调查容易过度摄入高脂肪饮食的正常体重杂交大鼠，确定它们是否在这些神经化学系统中表现出障碍；以及6)研究生命早期短暂的高脂肪饮食是否会对控制晚年高脂肪饮食摄入的外周和大脑系统产生长期影响。总而言之，这项拨款测试了一项新的假设，即高脂肪饮食本身可以通过涉及循环脂质、下丘脑肽和伏隔核DA的正反馈循环，促进暴饮暴食，最终导致饮食肥胖。

DESCRIPTION (provided by applicant): Dietary fat promotes overeating and obesity. Our recent studies demonstrate that ingestion of fat and the resulting rise in circulating lipids stimulate the hypothalamic peptide, galanin. In turn, higher galanin peptide further enhances food ingestion, particularly of high-fat diets. These findings lead to the novel suggestion that there exists a positive feedback loop, involving dietary fat, circulating triglycerides (TG) and hypothalamic peptides, which functions in a non-homeostatic manner to promote the overeating of fat-rich foods. This positive loop pre-empts and delays the effective onset of homeostatic negative feedback signals that normally limit food intake. Preliminary studies suggest that the opioid peptides, enkephalin and dynorphin, may also be involved in this process, acting in a remarkably similar way to galanin. Further, these hypothalamic peptides may be related to dopamine (DA) in the nucleus accumbens, which is known to enhance the motivation to eat. This new body of evidence leads us to propose the following six Specific Aims designed to test the specific role of hypothalamic peptide systems, accumbens DA, and lipids in promoting overeating of a high-fat diet. We plan: 1) To use acute, experimental paradigms to more precisely test in rats the involvement of circulating lipids in the well-known stimulatory effect of dietary fat on total caloric intake; 2) To firmly establish the effect of dietary fat and endogenous TG on specific hypothalamic peptides; 3) To study the role of accumbens DA in the effects of hypothalamic peptides and dietary fat on caloric intake; 4) To define the neural substrates and establish their essential nature in the phenomenon of fat-induced hyperphagia; 5) To investigate normal-weight outbred rats that are prone to overeating a fat-rich diet, to determine if they exhibit disturbances in these neurochemical systems; and 6) To examine whether brief periods of exposure to a high-fat diet early in life can have long-term impact on the peripheral and brain systems that control ingestion of a high-fat diet later in life. In summary, this grant tests the novel hypothesis that a high-fat diet itself can promote overeating and ultimately dietary obesity through a positive feedback loop involving circulating lipids, hypothalamic peptides and accumbens DA.