Brainstem Satiety Circuits and High Fat Diet Hyperphagia

描述(申请人提供)：肥胖是导致严重健康问题的主要因素。在过去的三四十年里，美国国内的肥胖率飙升，其中一个原因是高脂肪食物的消费增加。高脂肪饮食会导致暴饮暴食(吞噬过多)，这会促进易感人群的肥胖。在人类和大鼠身上都有证据表明，吞噬过多与降低对饮食脂肪饱腹感的敏感性有关，这是由于脑干饱腹感回路的参与减少。这项拟议的研究将进一步阐明这些回路的功能组织，强调共同表达催乳素释放的去甲肾上腺素能神经元在后脑中的潜在关键作用 多肽(PrRP)。这项拟议的工作与NIH肥胖研究战略计划一致，因为它侧重于调节食物摄入量和体重的生理神经机制。动物模型可以为导致人类肥胖的生理和行为因素提供关键的见解。此外，PrRP神经元位于人的尾侧脑干内，其分布与啮齿类动物相似。因此，实验结果将对理解饮食脂肪如何促进易受饮食诱导的吞噬症影响的人类吃得过多具有翻译意义，而其他暴露在相同饮食中的人仍然相对抵抗。我们认为，行为饱足感的产生至少部分是通过在孤束核的尾部内脏部分招募PrRP阳性神经元来产生的，并且这些神经元与脑干口服消化控制运动神经元有多突触联系。PrRP神经元直接接受来自胃肠道迷走神经传入的内脏感觉输入，中枢PrRP信号参与大鼠和小鼠摄食的动态平衡控制。这项拟议的研究将使用成年雄性大鼠来挑战最主要的假设，即饱腹感信号招募脑干PrRP信号通路来限制进食量。此外，我们还将检验这样一种假设，即高脂饮食会减弱PrRP介导的这种自然饱腹感过程，在出现吞噬过度的个别大鼠中，但在抵抗的大鼠中不会。我们认为，对高脂肪饮食的消耗性反应增加，至少部分是由于减弱了饱腹感信号诱导的脑干PrRP神经元的招募，这些神经元起到了限制食物摄入的作用。近交系Spraogue-Dawley大鼠是拟议研究的理想实验模型，因为大约50%的大鼠会出现行为吞噬症(即增加食量和每日食物摄入量)，从而在高脂肪饮食暴露期间促进体重增加，而其余的大鼠具有抵抗力，与正常对照饮食相比，它们的每日摄入量或体重没有增加更多。

DESCRIPTION (provided by applicant): Obesity is a major contributor to serious health problems. The incidence of obesity within the US has soared during the last 30-40 years, with a contributing cause being the increased consumption of high-fat foods. Diets high in fat can result in overeating (hyperphagia), which promotes obesity in susceptible individuals. There is evidence in both humans and rats that hyperphagia is related to reduce sensitivity to the satiating effect of dietary fat, due to reduced engagement of brainstem satiety circuits. The proposed research will further elucidate the functional organization of these circuits, highlightin a potentially critical role for hindbrain noradrenergic neurons that co-express prolactin-releasing peptide (PrRP). The proposed work is consistent with the NIH Strategic Plan for Obesity Research by its focus on physiological neural mechanisms that regulate food intake and body weight. Animal models can provide critical insights into physiological and behavioral factors that predispose humans to become obese. Further, PrRP neurons are located within human caudal brainstem in a distribution similar to that in rodent species. Thus, experimental outcomes will have translational implications for understanding how dietary fat promotes overeating in humans who are susceptible to diet-induced hyperphagia, while others exposed to the same diet remain relatively resistant. We propose that behavioral satiety is generated, at least in part, by recruitment of PrRP-positive neurons in the caudal visceral portion of the nucleus of the solitary tract, and that these neurons are polysynaptically linked to brainstem oral ingestive control motor neurons. PrRP neurons receive direct visceral sensory input from gastrointestinal vagal afferents, and central PrRP signaling is implicated in the homeostatic control of food intake in rats and mice. The proposed research will use adult male rats to challenge the overarching hypothesis that satiety signals recruit brainstem PrRP signaling pathways that limit meal size. In addition, we will test the hypothesis that a high-fat diet attenuates this natural PrRP-mediated satiety process in individual rats that develop hyperphagia, but not in resistant rats. We propose that increased consummatory responses to high fat diet are due, at least in part, to attenuated satiety signal-induced recruitment of brainstem PrRP neurons that act to limit food intake. Outbred Sprague-Dawley rats are an ideal experimental model for the proposed research, because approximately 50% develop behavioral hyperphagia (i.e., increased meal size and daily food intake) that promotes increased body weight gain during high fat diet exposure, whereas the remainder are resistant, and do not increase their daily intake or BW more than they do on normal control diet.