Dietary fatty acids, cell signals, and sucrose intake

膳食脂肪酸、细胞信号和蔗糖摄入量

• 批准号: 10046298
• 负责人: DIANNE FIGLEWICZ LATTEMANN
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046298
• 关键词: Acute; Address; Age; Astrocytes; Attitude; Behavior; Behavioral; Biological; Brain; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Cells; ChIP-seq; Chronic; Clinical; Corpus striatum structure; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diet; Diet Habits; Dietary Fats; Dietary Fatty Acid; Dietary Sucrose; Disease; Drug abuse; Eating; Energy Intake; Epigenetic Process; Fatty acid glycerol esters; Female; Food; Fructose; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Genetic Transcription; Goals; Harvest; High Fat Diet; Histones; Hyperphagia; Hypothalamic structure; Intake; Intervention; Life Style; Light; Link; Lysine; Measures; Metabolic; Metabolic Diseases; Methodology; Methylation; Middle Hypothalamus; Modification; Molecular; Motivation; Neuroglia; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Oleic Acids; Palate; Palmitates; Palmitic Acids; Pathology; Pathway interactions; Pattern; Pharmacology; Phenotype; Phosphorylation; Population; Proteins; Public Health; Publishing; Rattus; Recommendation; Reporting; Rewards; Risk; Role; Self Administration; Signal Transduction; Site; Stearates; Stimulus; Sucrose; Synapses; Testing; Therapeutic; Veterans; Weight Gain; calmodulin-dependent protein kinase II; cardiometabolism; cardiovascular risk factor; cell type; demethylation; design; diabetes risk; dietary; dietary control; drug of abuse; drug reward; histone modification; immunocytochemistry; insight; metabolic profile; military veteran; novel; preference; psychologic; relating to nervous system; social culture; sugar

The contribution of a high fat diet (HFD) to cardiovascular and metabolic pathology including risk for diabetes and obesity is well-documented. What has not been recognized is the influence of HFD on preference and intake of fructose-containing sugars, creating a behavioral component to the development of cardiometabolic pathology. Clinical and public health studies document the contribution of sucrose-containing foods and drinks to the onset of cardiometabolic disease, which are independent of obesity. We have focused upon the effect on HFD on motivation for sucrose, using a classic operant self-administration paradigm, and reported that a semi- chronic, moderate (31%) mixed-fat diet in rats increases motivation for sucrose intake relative to low fat- (LF) fed controls, an effect independent of increased adiposity. Now we have determined that the specific dietary fatty acids, stearate (STEAR) or palmitate (PALM) (but not oleic acid [OL]), increase sucrose motivation. We have begun to investigate the downstream consequences of dietary STEAR or PALM in the medial hypothalamus (HYP) and striatum (STR), key CNS sites for the sucrose motivation task. Because there is some commonality in neural substrates for different types of rewarding stimuli, we focused on gen-regulatory signals that have been functionally linked to drug-reward/motivation behaviors and found two significant changes. First, phosphorylation of the cell signal GSK3B is decreased in HYP and STR. Since phosphorylation inactivates GSK3B, the implication would be that GSK3B activity is increased, consistent with findings in the drug abuse field. Second, the epigenetic modification of Histone 3 (H3), H3K4me3 (tri-methylation at lysine-4), is decreased in the HYP. This modification (“mark”) is functionally linked with motivational behaviors for drugs of abuse. Because K3K4me3 is transcription-activating, the prediction would be that transcription of proteins which suppress motivation for food is decreased. The proposed studies follow on from these newly-published observations, to extend them, and to address the hypothesis that altered GSK3B and H3K4me3 contribute to or underlie the increased sucrose motivation caused by PALM diet. This will be tested in four Aims, with rats eating PALM, LF, or OL (a dietary fat control) diets. The first two Aims utilize identified pharmacologics which should decrease active GSK3B, or increase H3K4me3. Additionally, we will screen diet influences on an additional group of cell signals, and a set of histone 4 (H4) marks, all of which also have been linked to reward/motivation. In the third Aim we will focus on identifying cell-level targets for these signal changes, and will obtain gene expression data for the histone marks that are modified by the diets. We will use dual-immunocytochemistry to identify neurons, astrocytes, or glia co-expressing any of the altered cell signals or histone marks. We will use ChIP-Seq methodology to identify gene expression for genes that are linked to a specific histone mark, followed by quantitation and gene identification-path analysis. Finally, in a fourth Aim, we will determine diet effects on self- administration behavior and metabolic parameters in age-matched female rats. Collectively these studies will substantially add to our understanding of the cellular and behavioral effects of dietary fatty acids, in the context of a behavior that confers metabolic risk. Recent studies shed light on veterans’ obesity and the contribution of eating habits and attitudes, including a strong preference for sweets and overeating of palatable foods. Our new data should move this field towards the goal of identifying pathways for interventions, including dietary recommendations and psychological or pharmacotherapeutic treatment approaches.

高脂饮食（HFD）对心血管和代谢病理学（包括糖尿病风险）的影响 肥胖是有据可查的尚未认识到的是HFD对偏好和摄入量的影响 含果糖的糖，创造了一个行为组成部分的发展，心脏代谢 病理临床和公共卫生研究证明了含蔗糖食品和饮料的作用 与心脏代谢疾病的发病有关，这与肥胖无关。我们关注的是 HFD的动机蔗糖，使用经典的操作性自我管理范例，并报告说，一个半- 大鼠长期中等（31%）混合脂肪饮食相对于低脂（LF）增加了蔗糖摄入的动机 进食对照，与肥胖增加无关。现在我们已经确定，特定的膳食脂肪 酸，硬脂酸（STEAR）或棕榈酸（PALM）（但不是油酸[OL]），增加蔗糖动机。我们有 开始研究饮食STEAR或PALM在内侧下丘脑中的下游后果 (HYP)和纹状体（STR），关键的中枢神经系统网站的蔗糖动机任务。因为有一些共同点 在不同类型的奖励刺激的神经基质中，我们专注于基因调节信号， 与药物奖励/动机行为在功能上相关，并发现了两个显着变化。第一，磷酸化 细胞信号GSK 3B在HYP和STR中减少。由于磷酸化失活GSK 3B， 这意味着GSK 3B活性增加，与药物滥用领域的发现一致。第二、 组蛋白3（H3）的表观遗传修饰H3 K4 me 3（赖氨酸-4处的三甲基化）在HYP中减少。 这种修饰（“标记”）在功能上与药物滥用的动机行为有关。因为 K3 K4 me 3是转录激活的，预测将是抑制蛋白质的转录， 对食物的渴望降低了。拟议的研究是根据这些新发表的观察结果进行的， 扩展它们，并解决改变的GSK 3B和H3 K4 me 3有助于或基础的假设， PALM饮食引起的蔗糖动力增加。这将在四个目标中进行测试，大鼠食用PALM，LF， 或OL（膳食脂肪控制）饮食。前两个目的使用已确定的药理学， 活性GSK 3B，或增加H3 K4 me 3。此外，我们将筛选饮食对另一组细胞的影响， 信号和一组蛋白4（H4）标记，所有这些都与奖励/动机有关。第三 目的我们将集中于确定这些信号变化的细胞水平靶标，并将获得基因表达数据 被饮食改变的组蛋白标记。我们将使用双重免疫细胞化学来识别神经元， 星形胶质细胞或共表达任何改变的细胞信号或组蛋白标记的神经胶质。我们将使用ChIP-Seq 鉴定与特定组蛋白标记相关的基因的基因表达的方法， 定量和基因鉴定-通径分析。最后，在第四个目标中，我们将确定饮食对自我的影响， 给药行为和代谢参数。这些研究将 实质上增加了我们对膳食脂肪酸的细胞和行为影响的理解， 导致代谢风险的行为。最近的研究揭示了退伍军人的肥胖和 饮食习惯和态度，包括对甜食的强烈偏好和对可口食物的过度食用。我们的新 数据应该推动这一领域朝着确定干预途径的目标发展，包括饮食干预。 建议和心理或药物治疗方法。