Mechanisms of Programmed Gestational Hyperphagia

描述（由申请人提供）：目前，美国65%的成年人超重，五分之一的成年人肥胖，这是现代健康危机。在西方社会，肥胖及其相关疾病是导致死亡的主要原因，与高血压、冠心病、中风、糖尿病和癌症相关。儿童肥胖率达到20%，预示着成人肥胖率将进一步上升。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了解更少。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。我们的实验室研究模拟了人类肥胖编程，因为营养限制大鼠的IUGR后代表现出食欲增加，体重增加和肥胖的发展。我们提出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）；2)IUGR新生儿给予瘦素可防止程序性后代贪食。拟议的研究将确定受损饱腹感诱导的暴饮暴食的机制，重点关注瘦素和血清素厌氧性途径。我们将检查中央核反应，受体表达和信号通路，通过生理和药理学调节。神经元的内在特性将通过细胞外和细胞内电生理学来检查。我们将证实瘦素缺乏在程序性贪食中的主要作用，对比程序性和饮食性肥胖（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）的投射发展的相关性。我们将研究瘦素和芬氟拉明（d-fen）减少厌氧性反应的机制，包括受体特异性。我们将进一步测定ARC和PVN的反应性（即cFOS）以及饲喂/禁食和瘦素/d-fen后厌氧性/厌氧性信号因子和神经肽的表达。细胞外和细胞内电生理学研究将验证我们的假设，即MFR后代由于兴奋性输入减少/抑制性输入增加而表现出更高的POMC膜电位。最后，瘦素对对照组的拮抗以及对MFR后代补充瘦素的模型将证实我们提出的程序性贪食的机制。这些研究将提供重要的新信息，阐明氧源介导的摄食行为的编程机制，并为确定预防儿童和成人肥胖的策略提供模型。

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.