Leptin Signaling in Humans

描述（由申请人提供）： 肥胖已成为一个主要的公共卫生问题，特别是在退伍军人群体中，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，还没有明确有效和安全的药物用于长期肥胖治疗。此外，饮食和行为改变通常在肥胖个体中产生次优的体重减轻，这些肥胖个体可预测地在开始减轻体重后六个月开始恢复到基线体重。一种新兴的疗法是将瘦素和胰淀素共同施用于肥胖受试者，目前正在与胰淀素（Symlin（R））组合进行III期临床试验中测试这种治疗。然而，肥胖被认为是一种瘦素抵抗状态。当以替代剂量向患有瘦素缺乏和先天性脂肪萎缩的患者（即，尽管在患有这些病症的人中（例如，“瘦素敏感”个体）导致代谢参数（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的显著改善，但介导瘦素作用的确切细胞内信号传导途径仍是未知的。此外，瘦素信号转导缺陷是否在肥胖，瘦素抵抗的受试者瘦素抵抗的基础尚未研究。更好地理解这些途径不仅可以促进识别瘦素在细胞水平上的作用机制，而且还可以阐明瘦素在低瘦素状态下的作用机制和高瘦素血症状态下的瘦素抵抗机制（例如，肥胖症）。为了解决这些问题，我们建议在人体中进行干预性研究，以：1）确定体外、离体和体内施用瘦素是否可以诱导细胞内信号传导途径的活化（AMP激酶和其他途径）在脂肪细胞，肌肉和外周血单核细胞，和2）研究AMP激酶或瘦素受体下游的其它途径的失调是否可能是人类肥胖和/或糖尿病中瘦素抗性的机制。这样的研究也可以提供目标的治疗干预瘦素抵抗状态，如肥胖症，不仅阐明瘦素的作用途径，但也通过调查潜在的相互作用的瘦素与免疫和神经内分泌系统，可能会改变瘦素在体内的信号作用。这些信息将增加我们对瘦素生物学的理解，更具体地说，肥胖症中瘦素抵抗的信号传导途径，可能被证明对改善临床试验设计很重要，并且随着瘦素进一步被探索作为瘦素缺乏或瘦素抵抗状态的治疗，具有很高的治疗相关性。此外，阐明瘦素抵抗的细胞内信号通路可能最终导致发现瘦素增敏剂。这一建议可以通过Mantzlep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。本文提出的方法预计将产生新的机制见解，具有转化为改善的患者护理和治疗肥胖相关疾病状态、退伍军人群体中的公共卫生问题的潜力。

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.