Hypothalamic neurotransmitter systems & eating behavior

描述（由申请人提供）：膳食脂肪促进暴饮暴食和肥胖。 我们最近的研究表明，脂肪的摄入和循环脂质的增加刺激下丘脑肽，甘丙肽。 反过来，更高的甘丙肽进一步增强食物摄取，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，循环甘油三酯（TG）和下丘脑肽，其功能是以非稳态的方式促进过量进食富含脂肪的食物。 这种正循环预先阻止并延迟了通常限制食物摄入的稳态负反馈信号的有效发生。 初步研究表明，阿片肽脑啡肽和强啡肽也可能参与这一过程，其作用方式与甘丙肽非常相似。 此外，这些下丘脑肽可能与延髓核中的多巴胺（DA）有关，已知多巴胺能增强进食的动机。 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、多巴胺和脂质在促进高脂肪饮食过量中的具体作用。 我们计划：1）使用急性实验范例来更精确地测试大鼠中循环脂质参与膳食脂肪对总热量摄入的众所周知的刺激作用; 2）牢固地建立膳食脂肪和内源性TG对特定下丘脑肽的作用; 3）研究多巴胺在下丘脑肽和膳食脂肪对热量摄入的作用中的作用; 4）确定神经基质并确定其在脂肪诱导的摄食过多现象中的本质; 5）研究体重正常的远系繁殖大鼠，其易于过量进食富含脂肪的饮食，以确定它们是否表现出这些神经化学系统的紊乱;以及6）研究生命早期短暂接触高脂肪饮食是否会对控制生命后期摄入高脂肪饮食的外周和大脑系统产生长期影响。 总之，这项研究验证了一个新的假设，即高脂肪饮食本身可以通过涉及循环脂质、下丘脑肽和多巴胺的正反馈回路促进暴饮暴食并最终导致饮食性肥胖。

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.