Developmental mechanisms of leptin resistance

描述（由申请人提供）：该提案题为“瘦素耐药性的发育机制”，是DK57768-09竞争性更新的申请。我们之前的研究和该奖项下提出的研究的长期前景是了解损害瘦素作用和促进肥胖和代谢功能障碍的分子和神经机制。在目前的资助期内，我们重点研究了LepRb调节下丘脑生理和可能介导反馈抑制的机制。这项工作的主要结论包括Tyr985（以及其他LepRb信号）在LepRb作用衰减中的作用。现在有多种证据支持这样一种观点，即减弱LepRb信号的细胞过程有助于体内肥胖和瘦素抵抗。然而，额外的神经/发育机制有助于肥胖的开始。重要的是，围产期营养的改变启动了一个促进成年期肥胖和代谢综合征的程序。在这个关键的围产期窗口期，缺乏瘦素的作用或营养可用性的改变会破坏ARC神经元向其靶核的投射的发展，这表明瘦素和ARC回路的发展在早期代谢编程中可能起作用。然而，关于ARC预测的这些变化的许多问题仍有待解决。由于这些问题很难用标准工具解决，我们已经生成了一些新的转基因系统，使我们能够在这个应用中探索这些问题。在这个提案中，对各种知识和技术专长的需求要求Myers和Simerly实验室之间的密切合作。总之，我们将：(1)定义瘦素缺乏对瘦素调节的神经回路发育的功能后果。(2)围产期营养不良对瘦素调控的神经回路编程的影响。(3)确定瘦素介导的ARC神经回路发育编程的机制。这些研究将在调节能量稳态的神经回路的核心组成部分中确定瘦素和围产期营养状况改变的神经后果，并确定这些过程的潜在机制。从这些研究中获得的机制见解将定义可能导致代谢性疾病开始的过程。公共卫生相关性：瘦素是人体能量稳态和代谢的关键调节因子，瘦素作用受损可能导致多种代谢疾病。因此，了解可能干扰瘦素作用介导肥胖和代谢功能障碍的机制至关重要。因此，我们一直致力于确定瘦素受体LepRb介导瘦素作用反馈抑制的机制，并确定这些过程对体内肥胖的贡献。虽然这些过程有助于调节肥胖，但它们解释了肥胖的繁殖而不是发病。相比之下，围产期代谢程序显然是肥胖开始的重要基础。下丘脑瘦素反应回路的发育改变可能是这种围产期编程的中介。因此，我们建立了许多新的小鼠遗传模型，用来分析瘦素和营养改变对围产期下丘脑编程的机制和后果。

DESCRIPTION (provided by applicant): This proposal, entitled, "Developmental mechanisms of leptin resistance," is an application for competitive renewal of DK57768-09. The long-term outlook of our previous and proposed studies under this award is to understand molecular and neural mechanisms that impair leptin action and promote obesity and metabolic dysfunction. During the current funding period, we focused upon the mechanisms by which LepRb regulates hypothalamic physiology and may mediate feedback inhibition. Major conclusions from this work include the roles for Tyr985 (along with other LepRb signals) in the attenuation of LepRb action. Multiple lines of evidence now support the notion that cellular processes that attenuate LepRb signaling contribute to obesity and leptin resistance in vivo. Additional neural/developmental mechanisms contribute to the inception of obesity, however. Importantly, altered perinatal nutrition initiates a program that promotes obesity and metabolic syndrome in adulthood. Lack of leptin action or alterations in nutrient availability during this crucial perinatal window disrupts the development of projections from ARC neurons to their target nuclei, suggesting a potential role for leptin and the development of this ARC circuit in early metabolic programming. Many issues regarding these alterations in ARC projections remain to be addressed, however. As these issues are difficult to address with standard tools, we have generated a number of novel transgenic systems that will enable us to probe these issues in this application. The requirement for diverse intellectual and technical expertise in this proposal dictates an intimate collaboration between the Myers and Simerly labs. Together, we will: (1) Define the functional consequences of leptin deficiency on the development of leptin-regulated neural circuitry. (2) Examine the programming of leptin-regulated neural circuitry by perinatal undernutrition. (3) Determine the mechanisms that underlie the leptin-mediated developmental programming of the ARC neural circuitry. These studies will define the neural consequences of altered leptin and perinatal nutritional status within a core component of the neural circuitry that regulates energy homeostasis, as well as defining the mechanisms underlying these processes. The mechanistic insights derived from these studies will define processes that likely contribute to the inception of metabolic disease. PUBLIC HEALTH RELEVANCE: Leptin is a key regulator of body energy homeostasis and metabolism, and impaired leptin action may contribute to a variety of metabolic diseases. Understanding the mechanisms that may interfere with leptin action to mediate obesity and metabolic dysfunction is thus crucial. We have thus been working to define the mechanisms by which the leptin receptor, LepRb, mediates feedback inhibition of leptin action and to define the contribution of these processes to obesity in vivo. While these processes can contribute to the regulation of adiposity, they explain the propagation rather than the onset of obesity. In contrast, perinatal metabolic programming clearly underlies important aspects of the inception of obesity. Developmental alteration of hypothalamic leptin-responsive circuits represents a likely mediator of this perinatal programming. We have thus generated a number of novel mouse genetic models with which to analyze the mechanisms and consequences of perinatal hypothalamic programming by leptin and altered nutrition.