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 65% 的成年人超重，五分之一的人肥胖，这是一场现代健康危机。肥胖及其相关疾病是西方社会的首要死因，与高血压、冠心病、中风、糖尿病和癌症相关。 20%的儿童肥胖发生率预示着成人肥胖患病率将进一步上升。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更是了解甚少。流行病学研究证实，妊娠规划对肥胖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。我们实验室的研究模拟了人类肥胖编程，因为营养受限的大鼠母鼠的 IUGR 后代表现出食欲增加、体重增加和肥胖的发展。我们提出的研究将确定与母亲食物/营养限制（MFR）引起的胎儿 IUGR 相关的长期食欲可塑性的机制。我们假设 1) IUGR 导致胎儿/新生儿血浆瘦素水平受到抑制，从而损害厌食机制（例如神经回路、基因表达、细胞反应性）的发展，2) 对 IUGR 新生儿施用瘦素将预防程序性后代进食过多。拟议的研究将确定饱腹感受损引起的食欲亢进的机制，重点关注瘦素和血清素厌食途径。我们将通过生理和药理学调节来检查中枢核反应、受体表达和信号传导途径。将通过细胞外和细胞内电生理学检查内在神经元特性。我们将确认瘦素缺乏在程序性食欲亢进中的主要作用，对比程序性肥胖与饮食诱发肥胖 (DIO) 的机制，并探索新的预防策略。我们将首先确定 MFR 对新生儿瘦素激增的影响，以及瘦素水平与神经肽 Y (NPY) 发育和 POMC 从弓状 (ARC) 到室旁核 (PVN) 投射的相关性。我们将研究瘦素和芬氟拉明 (d-fen) 减少厌食反应的机制，包括受体特异性。我们将进一步确定 ARC 和 PVN 反应性（即 cFOS）以及进食/禁食和瘦素/d-fen 后厌食/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 后代将因兴奋性输入减少/抑制性输入增加而表现出 POMC 膜电位增加。最后，对照的瘦素拮抗模型以及对 MFR 后代的瘦素补充将证实我们提出的程序性进食过多的机制。这些研究将提供重要的新信息，阐明食欲原介导的摄入行为的编程机制，并提供一个模型来确定预防儿童和成人肥胖的策略。