Leptin Signaling in Humans

描述(由申请人提供)： 肥胖已经成为一个主要的公共卫生问题，特别是在退伍军人中，导致糖尿病、心血管疾病、恶性肿瘤和其他并发症的发病率和死亡率增加。到目前为止，还没有明显有效和安全的药物来治疗长期肥胖。此外，饮食和行为的改变通常会使肥胖者的体重下降到不理想的水平，可以预测的是，他们在开始减肥六个月后开始回到基线体重。一种新的疗法是对肥胖者联合使用瘦素和胰淀素，这一治疗目前正在与胰淀素(SYMLIN(R))第三阶段临床试验结合进行测试。然而，肥胖被认为是一种瘦素抵抗状态。瘦素缺乏和先天性脂肪萎缩患者(即“瘦素敏感”者)服用替代剂量的瘦素可显著改善代谢参数(包括胰岛素抵抗和/或高脂血症)以及神经内分泌和免疫功能，但在这些疾病的人类中，介导瘦素作用的确切细胞内信号通路尚不清楚。此外，肥胖、瘦素抵抗受试者中的瘦素信号缺陷是否是瘦素抵抗的基础还没有研究。更好地了解这些途径不仅有助于在细胞水平上识别瘦素的作用机制，而且还可以阐明瘦素在低瘦素状态下的作用机制以及在高瘦素血症状态下(如肥胖)的瘦素抵抗机制。为了解决这些问题，我们建议在人类中进行干预性研究：1)确定瘦素在体外、体外和体内给药是否可以诱导脂肪细胞、肌肉和外周血单核细胞中细胞内信号通路(AMP激酶和其他通路)的激活，以及2)研究AMP激酶或瘦素受体下游其他通路的失调是否可能是人类肥胖和/或糖尿病中瘦素抵抗的机制。这类研究不仅可以通过阐明瘦素的作用途径，还可以通过研究瘦素与免疫和神经内分泌系统的潜在相互作用，为瘦素抵抗状态(如肥胖)的治疗干预提供靶点。这些信息将增加我们对瘦素生物学的理解，更具体地说，将增加我们对肥胖中瘦素抵抗潜在的信号通路的理解，可能被证明对改进临床试验设计很重要，并且随着瘦素被进一步探索作为治疗瘦素缺乏或瘦素抵抗状态的方法，具有很高的治疗意义。此外，阐明瘦素抵抗的细胞内信号通路可能最终导致瘦素增敏剂的发现。这一建议可以通过Mantzoros实验室在瘦素生物学方面的专业知识来实现，该实验室是一个领先的研究小组，最近完成了几项关于人类瘦素生理学的关键研究。本文提出的方法有望产生新的机械性见解，有可能转化为改善肥胖相关疾病状态的患者护理和治疗，这是退伍军人群体中的公共卫生问题。 公共卫生相关性： 肥胖，定义为身体质量指数(BMI)为30公斤/平方米或更高，在美国已经上升到流行的比例。目前，大约30%的美国人患有肥胖症，预计到2030年，将有近50%的人口患有肥胖症。众所周知，发生胰岛素抵抗和2型糖尿病(DM)的风险随着体重的增加而增加。因此，人们正致力于了解肥胖与胰岛素抵抗和其他相关疾病状态的发展之间的关系。目前的研究将肥胖定性为对激素瘦素的抵抗状态，类似于已确定的发现，即2型糖尿病是对激素胰岛素的抵抗状态。本研究旨在阐明瘦素在细胞内信号通路激活中的作用，并找出在瘦素抵抗状态下可能功能失调的细胞内信号通路中的点。这可能为旨在治疗肥胖症和代谢紊乱的药物开发提供治疗靶点。

DESCRIPTION (provided by applicant): Obesity has become a major public health concern, particularly among the veteran population, leading to increased morbidity and mortality from diabetes, cardiovascular disease, malignancies, and other complications. To date, there is no clearly effective and safe medication for long-term obesity treatment. Furthermore, dietary and behavioral modification often produces suboptimal weight loss among obese individuals, who predictably start returning to baseline body weight six months after initiation of reduction in body weight. One emerging therapy is the co-administration of leptin and amylin to obese subjects, a treatment which is currently being tested in combination with Amylin (Symlin(R)) Phase III clinical trials. However, obesity is considered a leptin resistant state. While administration of leptin at replacement doses to patients with leptin deficiency and congenital lipoatrophy (i.e., 'leptin sensitive' individuals) results in dramatic improvements in metabolic parameters (including insulin resistance, and/or hyperlipidemia) as well as in neuroendocrine and immune function, the exact intracellular signaling pathways mediating leptin's action in humans with these conditions remain unknown. Furthermore, whether leptin signaling defects in obese, leptin resistant subjects underlies leptin resistance has not yet been studied. A better understanding of these pathways could not only facilitate the identification of mechanisms that underlie leptin's action at the cellular level, but may also elucidate mechanisms of leptin action in low-leptin states and leptin resistance in hyperleptinemic states (e.g., obesity). To address these questions, we propose to conduct interventional studies in humans to: 1) determine whether leptin administration in vitro, ex vivo, and in vivo can induce the activation of intracellular signaling pathways (AMP kinase and other pathways) in adipocytes, muscle, and peripheral blood mononuclear cells, and 2) investigate whether dysregulation of the AMP kinase or other pathways downstream of the leptin receptor could be a mechanism for leptin resistance in obesity and/or diabetes in humans. Such studies could also provide targets for therapeutic interventions in leptin resistant states such as obesity not only by elucidating pathways of leptin action, but also by investigating potential interactions of leptin with the immune and neuroendocrine systems that may alter the signaling effects of leptin in vivo. This information will increase our understanding of leptin biology and more specifically the signaling pathways underlying leptin resistance in obesity, may prove to be important for improved clinical trial design, and has high therapeutic relevance as leptin is explored further as a therapy for either leptin deficiency or leptin resistant states. Moreover, elucidation of the intracellular signaling pathways underlying leptin resistance may eventually lead to the discovery of leptin sensitizers. This proposal can be materialized by the expertise of the Mantzoros lab in leptin biology, a leading research group that has recently completed several pivotal studies in human leptin physiology. The approach proposed herein is expected to result in novel mechanistic insights with the potential for translation into improved patient care and treatment for obesity associated disease states, problems of public health in the veteran population. PUBLIC HEALTH RELEVANCE: Obesity, defined as a body mass index (BMI) of 30 kg/m2 or greater, has risen to epidemic proportions in the United States. Currently, approximately 30% of Americans are obese and it is expected that by 2030, close to 50% of the population will be obese (1). It is well known that the risk for the development of insulin resistance and type 2 diabetes mellitus (DM) increases incrementally with increasing body weight (2). Thus, considerable efforts are being devoted to understanding the relationship between obesity and the development insulin resistance and other associated disease states. Current research has characterized obesity as a state of resistance to the hormone leptin, similar to the established finding that type 2 DM is state of resistance to the hormone insulin. The research proposed herein aims to elucidate the role of leptin in the activation of intracellular signaling pathways and to identify points in intracellular signaling pathways which may be dysfunctional in states of leptin resistance. This may provide therapeutic targets for drug development aimed at treating obesity and metabolic disorders.