Metabolic and Epigenetic Effects of Maternal High Fat Diet in Obesity Prone Rats

母亲高脂肪饮食对肥胖倾向大鼠的代谢和表观遗传影响

• 批准号: 7991555
• 负责人: Timothy H Moran
• 金额: $ 2.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-11 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991555
• 关键词: Address; Adolescence; Adult; Affect; Animal Model; Behavioral; Body Weight; Cardiovascular Diseases; Characteristics; Clinical; Consumption; DNA Methylation Regulation; Data; Development; Diet; Discipline of Nursing; Endocrine; Environment; Epidemiology; Epigenetic Process; Etiology; Exposure to; Fatty acid glycerol esters; Fetal Growth Retardation; Fetus; Future; Genes; Goals; Health; Homeostasis; Hypertension; Hypothalamic structure; Insulin Resistance; Intervention; Lactation; Lead; Life; Life Style; Long-Term Effects; Mediating; Metabolic; Metabolic Diseases; Methylation; Modeling; Modification; Neonatal; Neural Pathways; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Nutritional status; Obesity; Organism; Phenotype; Predisposition; Pregnancy; Public Health; Rattus; Regulation; Risk; Role; Signal Transduction; Sprague-Dawley Rats; System; Testing; Time; Work; base; critical period; energy balance; feeding; metabolic abnormality assessment; nutrition; offspring; prevent; pup; research study; response

DESCRIPTION (provided by applicant): Obesity is a worldwide public health problem and recent work has suggested that alterations in maternal nutritional status may increase the risk of becoming obese. Epidemiological data have shown that maternal under-nutrition can lead to intrauterine growth retardation with long-term consequences to offspring including hypertension, cardiovascular disease, type 2 diabetes and obesity. Evidence is now emerging that maternal over-nutrition may have similar long-term consequences. Specifically, maternal consumption of a high fat diet, characteristic of the modern day Western lifestyle, has been shown to lead to metabolic disorders such as obesity and insulin resistance in offspring. The mechanisms mediating the consequences of maternal over-nutrition are not well understood. The overall goal of this proposal is to characterize the short- and long-term effects of maternal consumption of a high fat diet and resulting obesity in a polygenic diet induced rat model of obesity. The specific experiments address numerous aspects of the RFA in that they will: 1) characterize an animal model appropriate for the study of metabolic consequences of maternal high fat diet consumption and obesity, 2) define critical periods of susceptibility to metabolic perturbations on neural pathways involved in energy balance and 3) investigate the role of epigenetic changes as mediating mechanisms. The specific aims are: 1) To determine the developmental time course of behavioral and endocrine alterations resulting from maternal high fat diet consumption in obesity prone Sprague Dawley rats, 2) To test the hypothesis that maternal consumption of high fat diet produces alterations in hypothalamic neuropeptide signaling systems involved in energy balance that bias the developing pups toward obesity and metabolic disturbances, and 3) To determine whether high fat diet results in obesity and metabolic disturbances in offspring through epigenetic modifications. We hypothesize that genes that are critical to energy homeostasis are subject to regulation by DNA methylation and are differentially methylated in response to exposure to maternal high fat diet consumption and obesity. The results of these experiments will enhance our understanding of the etiology of obesity and metabolic disease ultimately allowing the development of rational clinical interventions for such conditions.

描述（由申请人提供）：肥胖是一个全球性的公共卫生问题，最近的研究表明，产妇营养状况的改变可能会增加肥胖的风险。流行病学数据显示，产妇营养不良可导致宫内发育迟缓，对后代造成长期后果，包括高血压、心血管疾病、2型糖尿病和肥胖。现在有证据表明，产妇营养过剩可能会产生类似的长期后果。具体来说，现代西方生活方式的特点——母亲摄入高脂肪饮食，已被证明会导致后代的代谢紊乱，如肥胖和胰岛素抵抗。介导产妇营养过剩后果的机制尚不清楚。本提案的总体目标是在多基因饮食诱导的肥胖大鼠模型中描述母体食用高脂肪饮食和导致肥胖的短期和长期影响。具体的实验涉及RFA的许多方面，因为它们将：1)表征适合研究母体高脂肪饮食摄入和肥胖代谢后果的动物模型，2)确定参与能量平衡的神经通路对代谢扰动的敏感性的关键时期，3)研究表观遗传变化作为中介机制的作用。具体目标是：1)为了确定肥胖易感大鼠母鼠高脂肪饮食导致的行为和内分泌改变的发育时间过程；2)为了验证母鼠高脂肪饮食导致参与能量平衡的下丘脑神经肽信号系统发生改变的假设，从而使发育中的幼鼠倾向于肥胖和代谢紊乱；3)通过表观遗传修饰确定高脂饮食是否会导致后代肥胖和代谢紊乱。我们假设，对能量稳态至关重要的基因受到DNA甲基化的调节，并在暴露于母体高脂肪饮食和肥胖的情况下发生差异甲基化。这些实验的结果将增强我们对肥胖和代谢性疾病的病因学的理解，最终允许针对这些疾病制定合理的临床干预措施。

项目成果

Maternal high-fat diet during gestation or suckling differentially affects offspring leptin sensitivity and obesity.

• DOI: 10.2337/db11-0957
• 发表时间: 2012-11
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Sun B;Purcell RH;Terrillion CE;Yan J;Moran TH;Tamashiro KL
• 通讯作者: Tamashiro KL

Prenatal stress or high-fat diet increases susceptibility to diet-induced obesity in rat offspring.

• DOI: 10.2337/db08-1129
• 发表时间: 2009-05
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Tamashiro KL;Terrillion CE;Hyun J;Koenig JI;Moran TH
• 通讯作者: Moran TH

Maternal stress and high-fat diet effect on maternal behavior, milk composition, and pup ingestive behavior.

• DOI: 10.1016/j.physbeh.2011.05.012
• 发表时间: 2011-09-01
• 期刊: PHYSIOLOGY & BEHAVIOR
• 影响因子: 2.9
• 作者: Purcell, Ryan H.;Sun, Bo;Pass, Lauren L.;Power, Michael L.;Moran, Timothy H.;Tamashiro, Kellie L. K.
• 通讯作者: Tamashiro, Kellie L. K.

Effects of high-fat diet exposure on learning & memory.

• DOI: 10.1016/j.physbeh.2015.06.008
• 发表时间: 2015-12-01
• 期刊: Physiology & behavior
• 影响因子: 2.9
• 作者: Cordner ZA;Tamashiro KL
• 通讯作者: Tamashiro KL

Early postweaning exercise improves central leptin sensitivity in offspring of rat dams fed high-fat diet during pregnancy and lactation.

• DOI: 10.1152/ajpregu.00566.2012
• 发表时间: 2013-11
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Bo Sun;Nu-Chu Liang;E. Ewald;R. Purcell;G. Boersma;Jian-qun Yan;T. Moran;K. Tamashiro