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的反应、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。

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.