Mechanisms of Programmed Gestational Hyperphagia

程序性妊娠期食欲过盛的机制

• 批准号: 8052762
• 负责人: Michael Glenn Ross
• 金额: $ 28.38万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052762
• 关键词: Accounting; Adipose tissue; Adult; Appetite Regulation; Birth; Cause of Death; Cell Nucleus; Cells; Child; Childhood; Colon Carcinoma; Coronary heart disease; Desire for food; Development; Diabetes Mellitus; Diet; Disease; Down-Regulation; Eating; Electrophysiology (science); Epidemic; Epidemiologic Studies; Exhibits; Fasting; Feeding behaviors; Fenfluramine; Fetal Growth; Food; Gene Expression; Growth; Health; Hormones; Human; Hyperphagia; Hypertension; Hypothalamic structure; Incidence; Infant; Knowledge; Label; Laboratories; Leptin; Leptin deficiency; Life; Low Birth Weight Infant; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Membrane Potentials; Metabolic syndrome; Modeling; Molecular; Neonatal; Neurons; Neuropeptides; Newborn Infant; Nutrient; Obesity; Overweight; Pathway interactions; Physiological; Plasma; Population; Pregnancy; Prevalence; Prevention; Prevention strategy; Production; Property; Rattus; Receptor Signaling; Regulation; Risk; Risk Factors; Role; STAT3 gene; Satiation; Secondary to; Series; Serotonin; Signal Pathway; Signal Transduction; Simulate; Societies; Specificity; Stroke; Supplementation; Techniques; Testing; Therapeutic; United States; Water consumption; Weight Gain; deprivation; design; extracellular; feeding; fetal; food restriction; in utero; increased appetite; malignant breast neoplasm; neuropeptide Y; novel; obesity in children; obesity prevention; offspring; paraventricular nucleus; patch clamp; prevent; programs; prophylactic; receptor; receptor expression; relating to nervous system; research study; response

DESCRIPTION (provided by applicant): Currently, 65% of adults in the United States are overweight and one in five is obese, representing a modern health crisis. Obesity and its related diseases are the leading cause of death in western society, with associated risks of hypertension, coronary heart disease, stroke, diabetes, and cancer. The 20% incidence of childhood obesity portends a further increase in the prevalence of adult obesity. There is limited understanding of the mechanisms for this epidemic and even less knowledge of effective approaches for obesity prevention. Epidemiologic studies confirm that gestational programming has contributed importantly to the epidemic of obesity, as preterm or intrauterine growth restricted (IUGR) infants have a paradoxical increased risk of adult metabolic syndrome. Studies in our laboratory model human obesity programming, as IUGR offspring of nutrient- restricted rat dams exhibit increased appetite, weight gain and the development of obesity. Our proposed studies will determine the mechanisms of long-term appetite plasticity associated with maternal food/nutrient restriction (MFR)-induced fetal IUGR. We hypothesize that 1) IUGR resulting in suppression of fetal/neonatal plasma leptin levels impairs the development of anorexigenic mechanisms (e.g., neurocircuitry, gene expression, cellular responsiveness), and 2) leptin administration to IUGR newborns will prevent programmed offspring hyperphagia. The proposed studies will determine mechanisms of impaired satiety-induced hyperphagia, focusing on the leptin and serotonin anorexigenic pathways. We will examine central nuclei responses, receptor expression and signaling pathways, by physiologic and pharmacologic modulation. Intrinsic neuronal properties will be examined by extra- and intracellular electrophysiology. We will confirm the primary role of leptin deficiency in programmed hyperphagia, contrast mechanisms of programmed versus diet-induced obese (DIO), and explore novel preventative strategies. We will initially determine the effect of MFR on the newborn leptin surge, and the correlation of leptin levels with development of neuropeptide-Y (NPY) and POMC projections from the arcuate (ARC) to the paraventricular nucleus (PVN). We will examine the mechanisms, including receptor specificity, of reduced anorexigenic responses to leptin and fenfluramine (d-fen). We will further determine ARC and PVN responsiveness (i.e., cFOS) and expression of anorexigenic/orexigenic signaling factors and neuropeptides following fed/fasting and leptin/d-fen. Extra- and intracellular electrophysiology studies will test our hypothesis that MFR offspring will demonstrate increased POMC membrane potential due to reduced excitatory/ increased inhibitory inputs. Finally, a model of leptin antagonism of controls, as well as leptin supplementation to MFR offspring will confirm our proposed mechanism of programmed hyperphagia. These studies will provide important new information elucidating mechanisms for programming of orexigenic-mediated ingestive behavior, and provide a model to determine strategies for the prevention of child and adult obesity.

描述（由申请人提供）：目前，美国有65％的成年人超重，五分之一是肥胖，代表了现代的健康危机。肥胖及其相关疾病是西方社会死亡的主要原因，与高血压，冠心病，中风，糖尿病和癌症相关的风险。儿童肥胖症的20％发生率预示着成年肥胖症患病率的进一步增加。对这种流行病的机制的理解有限，甚至对预防肥胖症的有效方法的了解更少。流行病学研究证实，由于早产或受宫内生长受限制（IUGR）婴儿具有矛盾的成人代谢综合征风险的矛盾风险，因此妊娠程序对肥胖症的流行作出了重要贡献。在我们的实验室模型中的研究人类肥胖计划中，养分受限大鼠大坝的IUGR后代表现出食欲增加，体重增加和肥胖的发展。我们提出的研究将确定与孕产妇食品/营养限制（MFR）诱导的胎儿IUGR相关的长期食欲可塑性的机制。我们假设1）IUGR抑制胎儿/新生儿血浆瘦素水平会损害厌食性机制的发展（例如，神经循环，基因表达，细胞反应能力，细胞反应能力）和2）对IUGR新生儿的瘦素给药会阻止编程的新生儿的生长症。拟议的研究将确定受损饱腹感诱导的心形的机制，重点是瘦素和5-羟色胺厌食途径。我们将通过生理和药理调节检查中央核反应，受体表达和信号通路。固有的神经元特性将通过细胞外电生理学检查。我们将确认瘦素缺乏症在编程的多晶状体，编程与饮食诱导的肥胖（DIO）的对比机制中的主要作用，并探讨了新颖的预防策略。我们最初将确定MFR对新生儿瘦素激增的影响，以及瘦素水平与神经肽-Y（NPY）和POMC投影的发展与从弧形（ARC）到室室核（PVN）的相关性。我们将研究降低脑毒素和芬氟拉明（D-fen）厌食症反应的机制，包括受体特异性。我们将进一步确定FED/禁食和瘦素/D-FEN后，我们将确定ARC和PVN响应性（即CFO）以及厌食/甲状腺素信号传导因子和神经肽的表达。细胞外电生理学研究将检验我们的假设，即MFR后代将由于兴奋性降低/抑制性输入增加而表明POMC膜的潜力增加。最后，对照组的瘦素拮抗作用以及对MFR后代补充瘦素的模型将证实我们提出的编程性超晶状体机制。这些研究将提供重要的新信息，以阐明针对甲状腺素介导的摄入行为的编程，并提供了一个模型来确定预防儿童和成人肥胖的策略。