Mechanisms of Programmed Gestational Hyperphagia

程序性妊娠期食欲过盛的机制

• 批准号: 7799747
• 负责人: Michael Glenn Ross
• 金额: $ 29.32万
• 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/7799747
• 关键词: ART protein; Abbreviations; Accounting; Adipose tissue; Adult; Age; Appetite Regulation; Birth; Breast; CARTPT gene; CRH gene; Cause of Death; Cell Nucleus; Cells; Child; Childhood; Colon Carcinoma; Coronary heart disease; Corticotropin-Releasing Hormone; Cytokine Inducible SH2-Containing Protein; Desire for food; Development; Diabetes Mellitus; Diet; Disease; Down-Regulation; Eating; Electrophysiology (science); Embryo; Epidemic; Epidemiologic Studies; Exhibits; Fasting; Feeding behaviors; Fenfluramine; Fetal Growth; Fetal Growth Retardation; Fetal Weight; Food; Gene Expression; Growth; Health; Hormones; Human; Hyperphagia; Hypertension; Hypothalamic structure; Incidence; Infant; Insulin Receptor; Janus kinase; Knowledge; Label; Laboratories; Leptin; Leptin deficiency; Life; Low Birth Weight Infant; Malignant Neoplasms; Mediating; Melanocortin 4 Receptor; Membrane Potentials; Metabolic syndrome; Modeling; Molecular; N-Methylaspartate; Neonatal; Neurons; Neuropeptides; Newborn Infant; Nutrient; Obesity; Overweight; Pathway interactions; Physiological; Plasma; Population; Pregnancy; Prevalence; Prevention; Prevention strategy; Pro-Opiomelanocortin; Production; Property; Prostate; Rattus; Regulation; Risk; Risk Factors; Role; STAT protein; Satiation; Secondary to; Series; Serotonin; Signal Pathway; Signal Transduction; Simulate; Societies; Specificity; Stroke; Structure of nucleus infundibularis hypothalami; Supplementation; Techniques; Testing; Therapeutic; United States; Water consumption; Weight Gain; deprivation; design; extracellular; feeding; fetal; food restriction; growth hormone secretagogue receptor; in utero; increased appetite; intraperitoneal; leptin receptor; maternal nutrient restriction; neuropeptide Y; novel; obesity in children; obesity prevention; offspring; paraventricular nucleus; patch clamp; postnatal; postsynaptic; prevent; programs; prophylactic; public health relevance; 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. PUBLIC HEALTH RELEVANCE: 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 breast, prostate and colon cancer. As childhood obesity is a major risk factor for adult obesity, the 20% incidence of childhood obesity portends a further increase in the prevalence of adult obesity. Obesity is central to the development of metabolic syndrome as a result of the unique production of adipose tissue hormones and cellular factors. There is limited understanding of the mechanisms for this epidemic and even less knowledge of effective approaches for obesity prevention. Our studies and others have demonstrated that gestational programming has contributed importantly to the epidemic of obesity. Appetite and satiety mechanisms develop during fetal life in utero to assure acquisition of food and water intake during the neonatal period. At birth, all mammalians offspring have developed functional ingestive mechanisms. Importantly, setpoints for appetite regulation are programmed or predetermined during late fetal life and/or the newborn period, such that low birth weight or intrauterine growth restricted (IUGR) offspring demonstrate markedly increased appetite, weight gain and the development of obesity. The proposed studies will determine mechanisms which account for increased appetite in growth restricted offspring. We hypothesize that 1) suppression of the obesity hormone leptin which occurs in IUGR offspring impairs the development of satiety mechanisms leading to offspring obesity, and 2) leptin administration to IUGR newborns will prevent programmed offspring obesity. 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65%的成年人超重，五分之一的人肥胖，代表着现代健康危机。肥胖及其相关疾病是西方社会的主要死亡原因，与高血压、冠心病、中风、糖尿病和癌症相关的风险。20%的儿童肥胖发生率预示着成人肥胖患病率的进一步增加。人们对这种流行病的机制了解有限，对预防肥胖的有效方法的了解更少。流行病学研究证实，妊娠规划对肥胖症的流行起着重要作用，因为早产或宫内生长受限（IUGR）婴儿患成人代谢综合征的风险反而增加。在我们的实验室模型中的研究人类肥胖规划，因为营养限制的大鼠母鼠的IUGR后代表现出食欲增加、体重增加和肥胖的发展。我们的研究将确定长期食欲可塑性与母体食物/营养限制（MFR）诱导胎儿IUGR相关的机制。我们假设1）IUGR导致胎儿/新生儿血浆瘦素水平的抑制损害了促生长机制的发展（例如，神经回路、基因表达、细胞反应性），和2）对IUGR新生儿施用瘦素将防止程序性后代摄食过多。拟议的研究将确定受损的饱腹感诱导的摄食过多的机制，重点是瘦素和血清素的促食欲途径。我们将通过生理和药理学调节来研究中枢核团反应、受体表达和信号通路。内在的神经元特性将通过细胞外和细胞内电生理学检查。我们将证实瘦素缺乏在程序性暴食中的主要作用，对比程序性肥胖与饮食诱导肥胖（DIO）的机制，并探索新的预防策略。我们将初步确定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从弓状核（ARC）到室旁核（PVN）的投射的相关性。我们将研究的机制，包括受体特异性，减少对瘦素和芬氟拉明（d-fen）的促肾上腺皮质激素反应。我们将进一步确定ARC和PVN响应性（即，cFOS）和进食/禁食和瘦素/d-fen后促食欲/促食欲信号传导因子和神经肽的表达。细胞外和细胞内电生理学研究将检验我们的假设，即MFR后代将表现出由于兴奋性降低/抑制性增加而导致的POMC膜电位增加。最后，一个模型的瘦素拮抗的控制，以及瘦素补充MFR后代将证实我们提出的程序性摄食过多的机制。这些研究将提供重要的新信息，阐明食欲介导的摄食行为的编程机制，并提供一个模型，以确定预防儿童和成人肥胖的策略。 公共卫生相关性：目前，美国65%的成年人超重，五分之一的人肥胖，这代表了现代健康危机。肥胖及其相关疾病是西方社会的主要死亡原因，与高血压、冠心病、中风、糖尿病以及乳腺癌、前列腺癌和结肠癌相关。由于儿童肥胖是成人肥胖的主要危险因素，20%的儿童肥胖发生率预示着成人肥胖患病率的进一步增加。肥胖是代谢综合征发展的核心，这是由于脂肪组织激素和细胞因子的独特产生。人们对这种流行病的机制了解有限，对预防肥胖的有效方法的了解更少。我们的研究和其他研究表明，妊娠期程序对肥胖的流行有重要贡献。食欲和饱腹感机制在胎儿宫内发育，以确保在新生儿期获得食物和水的摄入。在出生时，所有的马里亚人后代都已经发育出功能性的摄食机制。重要的是，在胎儿生命晚期和/或新生儿期期间编程或预定食欲调节的设定点，使得低出生体重或宫内生长受限（IUGR）后代表现出显著增加的食欲、体重增加和肥胖的发展。拟议的研究将确定导致生长受限后代食欲增加的机制。我们假设：1）抑制IUGR后代的肥胖激素瘦素会损害导致后代肥胖的饱腹感机制的发展，2）IUGR新生儿给予瘦素会预防后代的程序性肥胖。这些研究将提供重要的新信息，阐明食欲介导的摄食行为的编程机制，并提供一个模型，以确定预防儿童和成人肥胖的策略。