Cross sensitization of diet and alcohol on binge behaviors and metabolic dysfunction

饮食和酒精对暴饮暴食行为和代谢功能障碍的交叉敏感性

• 批准号: 10466806
• 负责人: Yuval Silberman
• 金额: $ 34.02万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10466806
• 关键词: Acute; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Animal Model; Animal Testing; Animals; Behavior; Behavioral; Behavioral Model; Brain region; Cell Nucleus; Cell physiology; Cells; Characteristics; Chronic; Chronic Disease; Clinical Research; Consumption; Data; Development; Diet; Disease; Disease Progression; Eating; Electrophysiology (science); Ethanol; Fatty acid glycerol esters; Food; Genetic; Glucose; Goals; Health; High Fat Diet; Human; Human Resources; Hyperglycemia; Impairment; Institutes; Insulin; Insulin Resistance; Intake; Laboratories; Link; Mediating; Mental Health; Metabolic; Metabolic dysfunction; Metabolism; Methods; Mission; Modeling; Morbid Obesity; Mus; Neuroimmune; Neurons; Neurosciences; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Outcome; Palate; Pancreas; Pattern; Physiology; Population; Positioning Attribute; Prediabetes syndrome; Predisposition; Reporting; Research; Rewards; Rodent; Signal Transduction; Site; Symptoms; Synapses; Techniques; Testing; United States; Vagus nerve structure; Work; alcohol effect; alcohol use disorder; base; binge drinking; binge type behavior; blood glucose regulation; brain cell; comorbidity; diet-induced obesity; dorsal motor nucleus; driving force; epidemiology study; genetic approach; glucose metabolism; glutamatergic signaling; heuristics; improved; insight; interest; mouse model; neural circuit; neuroinflammation; neuromechanism; neurotransmission; novel; obesity risk; patch clamp; postsynaptic; relating to nervous system; tool

Project Summary/Abstract Obesity and alcoholism are two of the most prevalent chronic diseases in the United States. These two diseases may be linked as obesity and alcoholism share common behavioral characteristics, such as binge intake, and are thought to utilize overlapping neural mechanisms. Additionally, obesity and alcoholism promote deficits in insulin and glucose metabolism, early predictors of Type II diabetes. The goal of this project is to understand how diets high in fat may interact with alcohol to worsen development and progression of both alcoholism and diet-induced obesity related metabolic dysfunction in mouse models. Specifically, we will examine how eating patterns can produce binge-type high fat diet food intake that may cross-sensitize to binge alcohol consumption in a novel behavioral model of co-morbid diet and ethanol interactions in mice. We will then examine the neurocircuitry involved in these binge intake patterns and determine the mechanisms by which high fat diets and alcohol modulate critical brain cell populations. Based on our preliminary data, we propose that high fat diet and alcohol consumption increase neuronal activation in the central nucleus of the amygdala via modulation of neuroimmune cell function. Finally, we will examine the impact of co-morbid high fat diet and alcohol consumption on insulin and glucose function and metabolism. In doing so, we will determine the mechanisms by which key neurocircuitry involved in the central control on insulin release are altered by high fat diet and alcohol. Specifically, we will be examining the mechanisms by which high fat diet and alcohol consumption inhibit the activity of neuronal populations in the dorsal motor nucleus of the vagus nerve that project to the pancreas and how this cell population is modulated by central amygdala inputs. These research questions will be tested with a novel combination of electrophysiologic, immunohistochemical, opto- and chemo- genetic, behavioral, and whole-animal physiology methods not typically seen within a single application and examine diet and alcohol changes from the cellular level to whole animal function. These studies will be of significant interest to the mission of the National Institute of Alcohol Abuse and Alcoholism, and are of important relevance to FOA PA-17-211. Successful completion of these studies will provide new understanding of the mechanisms involved in the disease progression of obesity and alcoholism as well as uncover new potential targets for the treatment of both disorders, both singularly and in co-morbid situations.

项目摘要/摘要 肥胖和酗酒是美国最常见的两种慢性病。这两种疾病 可能是因为肥胖和酗酒有共同的行为特征，如暴饮暴食，以及 被认为利用重叠的神经机制。此外，肥胖和酗酒会增加人体的营养不良。 胰岛素和葡萄糖代谢，II型糖尿病的早期预测因素。这个项目的目标是了解 高脂肪饮食如何与酒精相互作用以恶化酒精中毒的发展和进展 饮食诱导肥胖相关代谢功能障碍的小鼠模型。具体地说，我们将研究如何吃 模式可以产生狂欢类型的高脂肪饮食食物摄入，这可能会对狂欢的酒精交叉敏感 小鼠饮食和酒精共病交互作用的新行为模型中的消费。到时候我们会的 检查这些暴饮暴食模式中涉及的神经回路，并确定其机制 高脂肪饮食和酒精会调节关键的脑细胞数量。根据我们的初步数据，我们建议 高脂饮食和饮酒增加了杏仁中央核神经元的激活 通过调节神经免疫细胞功能。最后，我们将研究共病高脂饮食的影响。 以及饮酒对胰岛素和葡萄糖功能及代谢的影响。在此过程中，我们将确定 HIGH改变中枢控制胰岛素释放的关键神经回路的机制 脂肪饮食和酒精。具体地说，我们将研究高脂肪饮食和酒精 消费抑制迷走神经背侧运动核神经元群的活动 投射到胰腺，以及中央杏仁核的输入如何调节这个细胞群。这些研究 问题将通过电生理、免疫组织化学、光学和免疫组化的新组合进行测试。 化学遗传学、行为学和全动物生理学方法通常不是单一的 应用和检验饮食和酒精从细胞水平到整体动物功能的变化。这些 研究将对国家酒精滥用和酒精中毒研究所的使命产生重大意义， 并与FOA PA-17-211具有重要的相关性。这些研究的成功完成将提供新的 了解肥胖和酒精中毒的疾病进展机制以及 发现治疗这两种疾病的新的潜在靶点，既有单独的，也有共病的。