Mechanisms of Programmed Gestational Hyperphagia

描述(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。在西方社会，肥胖及其相关疾病是主要的死亡原因，伴随着高血压、冠心病、中风、糖尿病和癌症的相关风险。20%的儿童肥胖率预示着成人肥胖率将进一步上升。对这一流行病的机制了解有限，对预防肥胖症的有效方法更是知之甚少。流行病学研究证实，妊娠规划对肥胖的流行起到了重要作用，因为早产儿或宫内生长受限(IUGR)婴儿患成人代谢综合征的风险增加，这是自相矛盾的。在我们的实验室模型人类肥胖规划的研究中，营养受限大鼠的IUGR后代表现出食欲增加、体重增加和肥胖的发展。我们建议的研究将确定与母体食物/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导致胎儿/新生儿血浆瘦素水平的抑制损害了厌食机制的发展(例如，神经回路、基因表达、细胞反应)，以及2)IUGR新生儿给予瘦素可以防止程序性后代过度吞噬。拟议中的研究将确定饱腹感受损诱导的过度吞噬的机制，重点是瘦素和5-羟色胺的厌氧途径。我们将通过生理和药物调节来研究中枢核反应、受体表达和信号通路。神经元的内在特性将通过细胞外和细胞内的电生理学进行检测。我们将确认瘦素缺乏在程序性高吞噬中的主要作用，对比程序性和饮食诱导肥胖(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)和从弓状核(ARC)到室旁核(PVN)的POMC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。我们将进一步测定ARC和PVN的反应性(即CFO)，以及在FED/空腹和瘦素/d-fen后厌氧/厌氧信号因子和神经肽的表达。细胞外和细胞内的电生理学研究将检验我们的假设，即MFR后代将由于兴奋性/抑制性输入的减少而表现出POMC膜电位的增加。最后，对照组的瘦素拮抗模型以及对MFR子代补充瘦素将证实我们提出的程序性吞噬过度的机制。这些研究将提供重要的新信息，阐明食欲素介导的摄食行为的编程机制，并提供一个模型来确定预防儿童和成人肥胖的策略。

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.