Developmental insulin/leptin signaling determines set-point of the adult melanoco

描述（由申请方提供）：在成年生殖活跃女性中，代谢紊乱（如肥胖和II型糖尿病）的患病率和传播持续增加。除了这些疾病对成年人的有害影响外，人们越来越意识到孕妇代谢紊乱对其后代的潜在长期负面影响。事实上，已经有人提出，在子宫内和出生后早期由肥胖和/或糖尿病母亲喂养的儿童中，慢性疾病的发展可能会大大加速。这种早期编程的潜在分子机制仍然不清楚。中枢神经系统，特别是下丘脑弓状核，已经成为控制代谢的行为和内分泌方面的关键部位之一。我们的初步观察结果显示，弓状核神经元特定亚群中某些基因的破坏导致了代谢表型改变的出现，与肥胖或糖尿病母亲的后代中出现的代谢表型没有什么不同。我们的中心假设源于这些调查，并提出，改变细胞内信号弓状核黑皮质素系统引发的胰岛素是一个主要组成部分，在随后的代谢紊乱的病因。我们将通过对野生型和基因改变小鼠的研究进一步加强这一假设。我们将解决以下具体目标：目的1确定肥胖/糖尿病母亲的后代中AgRP和POMC神经元的细胞变化。目的2研究肥胖/糖尿病母亲子代AgRP和POMC神经元对喂养、禁食、瘦素、胰岛素和葡萄糖的反应。目的3探讨弓状核神经元亚群胰岛素和瘦素信号转导靶向突变对肥胖/糖尿病母亲后代神经回路发育和代谢表型的影响。上述目标的实现将为更好地理解肥胖和糖尿病母亲子宫内环境相关代谢紊乱的病因提供分子解释。公共卫生相关性：拟议项目将分析怀孕对后代肥胖和糖尿病发展的作用。这是一个高度相关的医学研究领域，因为大多数妇女在怀孕期间超重，这可能是肥胖症流行和II型糖尿病患病率增加的主要原因。

DESCRIPTION (provided by applicant): In adult, reproductively active females, there is a continued increase in prevalence and propagation of metabolic disorders, such as obesity and type II diabetes. Beyond the harmful effects of these disorders on the adult population, there is increasing awareness of the potential long lasting negative influence of metabolic disorders of pregnant mothers on their offspring. Indeed, arguments have been made that chronic disease development maybe dramatically accelerated in children who were nursed in utero and early post-natally by obese and/or diabetic mothers. The underlying molecular mechanism of this early programming remains ill- defined. The central nervous system, and the hypothalamic arcuate nucleus in particular, has emerged as one of the key sites from which both behavioral and endocrine aspects of metabolism are governed. Our preliminary observations revealed the disruption of certain genes in specific subpopulation of arcuate nucleus neurons underlie the emergence of altered metabolic phenotypes not dissimilar to those emerging in offspring of obese or diabetic mothers. Our central hypothesis stem from these investigations and propose that altered intracellular signaling in the arcuate nucleus melanocortin system triggered by insulin is a major component in the etiology of subsequent metabolic disturbances. We will further strengthen this hypothesis by investigations proposed here on wild type and genetically altered mice. We will address the following specific aims: Aim 1 Determine the cellular changes in AgRP and POMC neurons in the offspring of obese/diabetic mothers. Aim 2 Unveil the responses of AgRP and POMC neurons to feeding, fasting, leptin, insulin and glucose in the offspring of obese/diabetic mothers. Aim 3 Assess the effect of targeted mutations of insulin and leptin signaling in subpopulations of arcuate nucleus neurons on circuit development and metabolic phenotype of offspring derived from obese/diabetic mothers. The execution of the above aims will proved molecular explanations for the better understanding of the etiology of metabolic disorders in association with in utero environment of obese and diabetic mothers. PUBLIC HEALTH RELEVANCE: The proposed project will analyze the role of pregnancy on the development of obesity and diabetes of the offspring. This is a highly relevant area of medical research as the majority of women are overweight during pregnancy, which may be a main reason for the increasing obesity epidemic and the increased prevalence of type II diabetes.