Leptin Signaling in Humans

人类瘦素信号传导

基本信息

批准号：
8698369
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
项目类别：
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/8698369
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 research study species difference therapeutic target

项目摘要

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.

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。迄今为止，还没有明确有效且安全的长期肥胖治疗药物。此外，饮食和行为改变通常会导致肥胖个体的体重减轻效果不佳，可以预见的是，肥胖个体在开始减轻体重六个月后开始恢复到基线体重。一种新兴疗法是向肥胖受试者联合施用瘦素和胰淀素，目前正在结合胰淀素 (Symlin(R)) III 期临床试验对这种疗法进行测试。然而，肥胖被认为是瘦素抵抗状态。虽然对瘦素缺乏和先天性脂肪萎缩的患者（即“瘦素敏感”个体）给予替代剂量的瘦素可显着改善代谢参数（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，在患有这些疾病的人类中，介导瘦素作用的确切细胞内信号传导途径仍然未知。此外，尚未研究肥胖、瘦素抵抗受试者的瘦素信号传导缺陷是否是瘦素抵抗的基础。更好地了解这些途径不仅可以促进在细胞水平上识别瘦素作用机制，还可以阐明低瘦素状态下的瘦素作用机制和高瘦素血症状态（例如肥胖）下的瘦素抵抗机制。为了解决这些问题，我们建议在人体中进行介入研究：1) 确定在体外、离体和体内施用瘦素是否可以诱导脂肪细胞、肌肉、肌肉和细胞中细胞内信号通路（AMP 激酶和其他通路）的激活。和外周血单核细胞，2) 研究 AMP 激酶或瘦素受体下游其他途径的失调是否可能是人类肥胖和/或糖尿病瘦素抵抗的机制。此类研究还可以为瘦素抵抗状态（例如肥胖）的治疗干预提供目标，不仅可以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，从而改变瘦素在体内的信号传导作用。这些信息将增加我们对瘦素生物学的理解，更具体地说，是对肥胖中瘦素抵抗的信号通路的理解，可能被证明对改进临床试验设计很重要，并且随着瘦素作为瘦素缺乏或瘦素治疗的进一步探索，具有很高的治疗相关性。瘦素抵抗状态。此外，阐明瘦素抵抗的细胞内信号通路可能最终导致瘦素敏化剂的发现。这项提议可以通过曼佐罗斯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，最近完成了人类瘦素生理学的几项关键研究。本文提出的方法预计将产生新颖的机制见解，并有可能转化为改善患者护理和肥胖相关疾病状态、退伍军人群体公共卫生问题的治疗。