Leptin Signaling in Humans

人类瘦素信号传导

• 批准号: 8244948
• 负责人: CHRISTOS S MANTZOROS
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244948
• 关键词: Acute; Address; Adipocytes; Adipose tissue; American; Animals; Behavior Therapy; Biological; Biology; Blood; Body Weight; Body Weight decreased; Body mass index; Brain; Cardiovascular Diseases; Cell Line; Cells; Chronic; Clinical Trials Design; Defect; Development; Diabetes Mellitus; Diet Modification; Disease; Dose; Drug Design; Eating; Environment; Epidemic; Exposure to; Fatty acid glycerol esters; Future; Hormones; Human; Human Cell Line; Hyperlipidemia; Hypothalamic structure; Immune; Immune system; In Vitro; Individual; Insulin; Insulin Resistance; Insulin Signaling Pathway; Intracellular Signaling Proteins; Laboratories; Lead; Leptin; Leptin deficiency; Leptin resistance; Lipoatrophy; Liver; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Morbidity - disease rate; Mus; Muscle; Muscle Fibers; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Obesity associated disease; Pathway interactions; Patient Care; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase III Clinical Trials; Physiology; Pilot Projects; Population; Public Health; Publishing; Rattus; Regulation; Reporting; Research; Resistance; Risk; Rodent; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Tissues; Translations; United States; Veterans; Weight Gain; Woman; Work; adenylate kinase; base; clinically significant; diabetic; drug development; human subject; human tissue; immune function; improved; in vivo; insight; insulin signaling; islet amyloid polypeptide; leptin receptor; men; mortality; novel; obesity treatment; public health relevance; research study; species difference; therapeutic target

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.

描述（由申请人提供）： 肥胖已成为一个主要的公共卫生问题，尤其是在退伍军人人口中，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。迄今为止，没有明显有效且安全的药物用于长期肥胖治疗。此外，饮食和行为修改通常会在肥胖个体中产生次优的体重减轻，这些人可以预见，在体重减轻后六个月后，他们可以预见地开始重返基线体重。一种新兴的疗法是将瘦素和淀粉蛋白与肥胖受试者共同给药，目前正在与淀粉酶（Symlin（r））III期临床试验结合进行测试。但是，肥胖被认为是瘦素耐药性态。 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.此外，尚未研究瘦素耐瘦素的耐瘦素耐药性的瘦素信号传导缺陷。对这些途径的更好理解不仅可以促进瘦素在细胞水平上作用的机制的鉴定，而且还可以阐明在低leptin状态下瘦素作用的机制和在高肠态中的瘦素耐药性（例如肥胖）。 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受体可能是肥胖症和/或人类糖尿病中瘦素抗性的机制。此类研究还可以为瘦素耐药状态（例如肥胖症）提供治疗性干预措施，这不仅是通过阐明瘦素作用的途径，而且还通过研究瘦素与免疫和神经内分泌系统的潜在相互作用，从而可以改变VIVO中瘦素的信号传导作用。该信息将增加我们对瘦素生物学的理解，更具体地说是肥胖症中瘦素耐药性的信号传导途径，可能对改善临床试验设计很重要，并且具有高度治疗的相关性，因为瘦素被作为瘦素缺乏症或耐瘦素耐药态的疗法进一步探索。此外，阐明细胞内信号通路的固定性耐药性最终可能导致瘦素敏化剂的发现。该提案可以通过Mantzoros Lab在Leptin Biology中的专业知识来实现​​，这是一个领先的研究小组，该小组最近完成了人类瘦素生理学的几项关键研究。预计本文提出的方法将导致新颖的机械见解，并有可能转化为肥胖相关疾病状态的患者护理和治疗，这是退伍军人人口中的公共卫生问题。 公共卫生相关性： 肥胖症定义为30 kg/m2或更高的体重指数（BMI），在美国已经升至流行比例。目前，约有30％的美国人肥胖，预计到2030年，将近50％的人口将肥胖（1）。众所周知，随着体重的增加，胰岛素抵抗和2型糖尿病（DM）的风险逐渐增加（2）。因此，正在努力理解肥胖与胰岛素抵抗与其他相关疾病状态之间的关系。当前的研究将肥胖症描述为对激素瘦素的抗性状态，类似于确定的发现2型DM是对激素胰岛素的抗性状态。本文提出的研究旨在阐明瘦素在细胞内信号通路的激活中的作用，并识别细胞内信号通路中的点，而细胞内信号传导途径中可能在瘦素抗性状态下可能功能失调。这可能为旨在治疗肥胖症和代谢疾病的药物开发提供治疗靶标。