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.

高脂肪饮食 (HFD) 对心血管和代谢病理学（包括糖尿病风险）的影响 肥胖对饮食偏好和摄入量的影响尚未得到充分认识。 含果糖的糖，为心脏代谢的发展创造了行为成分 病理学和公共卫生研究记录了含蔗糖食品和饮料的贡献。 我们关注的是与肥胖无关的心脏代谢疾病的发生。 HFD 使用经典的操作性自我管理范式探讨蔗糖的动机，并报告说，半 相对于低脂饮食，慢性、中度（31%）混合脂肪饮食会增加大鼠摄入蔗糖的动机（LF） 喂养对照，其影响与肥胖的增加无关。现在我们已经确定了特定的膳食脂肪酸。 硬脂酸 (STEAR) 或棕榈酸 (PALM)（但不包括油酸 [OL]），可增加蔗糖动力。 开始研究饮食 STEAR 或 PALM 对内侧下丘脑的下游影响 （HYP）和纹状体（STR），蔗糖激励任务的关键中枢神经系统位点，因为有一些共同点。 在不同类型奖励刺激的神经基质中，我们关注的是基因调节信号 在功能上与药物奖励/动机行为相关，并发现两个显着的变化，首先是磷酸化。 由于磷酸化使 GSK3B 失活，因此 HYP 和 STR 中的细胞信号 GSK3B 降低。 这意味着 GSK3B 活性增加，这与药物滥用领域的研究结果一致。 组蛋白 3 (H3)、H3K4me3（赖氨酸 4 处的三甲基化）的表观遗传修饰在 HYP 中减少。 这种修饰（“标记”）在功能上与滥用药物的动机行为相关。 K3K4me3 具有转录激活作用，预测抑制蛋白质的转录 根据这些新发表的观察结果，拟议的研究减少了。 扩展它们，并解决改变 GSK3B 和 H3K4me3 有助于或构成其基础的假设 PALM 饮食引起的蔗糖动机增加 这将在四个目标中进行测试，老鼠吃 PALM、LF、 或 OL（饮食脂肪控制）饮食的前两个目标是使用已确定的药物来减少饮食。 激活 GSK3B，或增加 H3K4me3 此外，我们将筛选饮食对另一组细胞的影响。 信号和一组组蛋白 4 (H4) 标记，所有这些也与第三个中的奖励/动机相关。 目标我们将专注于识别这些信号变化的细胞水平目标，并将获得基因表达数据 对于饮食改变的组蛋白标记，我们将使用双免疫细胞化学来识别神经元， 星形胶质细胞或神经胶质细胞共表达任何改变的细胞信号或组蛋白标记，我们将使用 ChIP-Seq。 识别与特定组蛋白标记相关的基因表达的方法，然后 最后，在第四个目标中，我们将确定饮食对自我的影响。 这些研究将共同​​研究年龄匹配的雌性大鼠的给药行为和代谢参数。 大大增加了我们对膳食脂肪酸对细胞和行为影响的理解 最近的研究揭示了退伍军人的肥胖及其影响。 饮食习惯和态度，包括对甜食的强烈偏好和过量食用我们的新食物。 数据应推动这一领域朝着确定干预措施途径（包括饮食干预）的目标迈进。 建议和心理或药物治疗方法。