Brainstem Satiety Circuits and High Fat Diet Hyperphagia

脑干饱腹感回路和高脂肪饮食贪食

• 批准号: 9462292
• 负责人: Linda M Rinaman
• 金额: $ 33.28万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9462292
• 关键词: Acute; Adult; Animal Model; Attenuated; Behavior; Behavioral; Body Weight; Brain Stem; Cells; Cholecystokinin; Chronic; Consummatory Behavior; Consumption; Deglutition; Development; Diet; Dietary Fats; Dose; Eating; Experimental Models; Fatty acid glycerol esters; Food; Gastrointestinal tract structure; Genes; Health; High Fat Diet; Human; Hyperphagia; Hypothalamic structure; Incidence; Individual; Intake; Laboratory Rat; Link; Maintenance; Mastication; Mediating; Motor Neurons; Motor output; Mus; Neonatal; Neurons; Nucleus solitarius; Obesity; Operative Surgical Procedures; Oral; Outcome; Outcomes Research; Pathway interactions; Pattern; Peptide Signal Sequences; Physiological; Play; Predisposing Factor; Process; Prosencephalon; Rattus; Recruitment Activity; Regulation; Research; Resistance; Rest; Rodent; Role; Satiation; Signal Pathway; Signal Transduction; Sincalide; Small Interfering RNA; Sprague-Dawley Rats; Strategic Planning; Technology; Testing; Thinness; United States National Institutes of Health; Visceral; Weight Gain; Work; attenuation; behavioral response; energy balance; feeding; gastrointestinal; hindbrain; insight; knock-down; male; motor control; neural circuit; neuromechanism; neurotropic virus; noradrenergic; oral motor; programs; prolactin-releasing peptide; public health relevance; relating to nervous system; response; sensory input

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.

描述（由申请人提供）：肥胖是严重健康问题的一个主要原因。过去 30-40 年间，美国肥胖症发病率急剧上升，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，从而促进易感人群肥胖。在人类和大鼠中都有证据表明，由于脑干饱腹感回路的参与减少，进食过多与降低对膳食脂肪饱腹感的敏感性有关。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后脑去甲肾上腺素能神经元的潜在关键作用 肽（PrRP）。拟议的工作与美国国立卫生研究院肥胖研究战略计划一致，重点关注调节食物摄入和体重的生理神经机制。动物模型可以提供对导致人类肥胖的生理和行为因素的重要见解。此外，PrRP 神经元位于人类尾部脑干内，其分布与啮齿类动物相似。因此，实验结果将对理解膳食脂肪如何促进易受饮食引起的暴饮暴食的人类暴饮暴食，而其他接触相同饮食的人保持相对抵抗力具有转化意义。 我们认为，行为饱腹感至少部分是通过募集孤束核尾部内脏部分的 PrRP 阳性神经元产生的，并且这些神经元与脑干口腔摄入控制运动神经元多突触相关。 PrRP 神经元接收来自胃肠道迷走神经传入的直接内脏感觉输入，中枢 PrRP 信号传导参与大鼠和小鼠食物摄入的稳态控制。拟议的研究将使用成年雄性大鼠来挑战一个总体假设，即饱腹感信号会招募限制膳食量的脑干 PrRP 信号通路。此外，我们将测试这样一个假设：高脂肪饮食会减弱这种自然的 PrRP 介导的饱腹感过程，在出现摄食过多的个体大鼠中，但在抵抗大鼠中则不会。我们认为，对高脂肪饮食的完成反应的增加至少部分是由于饱腹感信号减弱引起的脑干 PrRP 神经元的募集，这些神经元起到限制食物摄入的作用。近交系 Sprague-Dawley 大鼠是拟议研究的理想实验模型，因为大约 50% 的大鼠会出现行为性食欲亢进（即增加膳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，而其余的则具有抵抗力，并且不要比正常控制饮食增加更多的每日摄入量或体重。