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Leptin resistance: 1 mechanism underlying age-related obesity

瘦素抵抗：年龄相关性肥胖的一种潜在机制

基本信息

批准号：
7475658
负责人：
PHILIP J SCARPACE
金额：
$ 34.24万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-15 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7475658
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Accounting Acute Address Adipose tissue Adult Age American Animal Model Animals Appetite Depressants Attenuated Binding Body Weight Body Weight decreased Body fat Brown Fat Caloric Restriction Cholesterol Chronic Daily Data Dependovirus Development Diabetes Mellitus Diet Dose Down-Regulation Eating Energy Metabolism Fasting Fatty acid glycerol esters Fibrinogen Food Futile Treatments Gene Delivery Gene Expression Genetic Glucose Homeostasis Hormones Human Hyperlipidemia Hypertension Hypothalamic structure IRS1 gene IRS2 gene Inbred BN Rats Injection of therapeutic agent Insulin Insulin Receptor JAK2 gene Janus kinase 2 LY294002 Lead Leptin Leptin resistance Life Mediating Melanocyte stimulating hormone Modeling Monitor Muscle Nature Non-Insulin-Dependent Diabetes Mellitus Numbers Nutrition Disorders Obesity Oxygen Consumption POMC gene Palmitates Pathway interactions Pattern Peripheral Phosphorylation Principal Investigator Pro-Opiomelanocortin Protein Tyrosine Kinase Proteins Public Health Rate Rattus Receptor Mediated Signal Transduction Receptor Signaling Recombinant adeno-associated virus (rAAV)Recombinants Research Personnel Resistance Rodent Rodent Model Role STAT3 gene Serum Signal Pathway Signal Transduction Societies Testing Tetanus Helper Peptide Time Tissues Upper arm Week Weight Gain Work age related aged attenuation day desensitization feeding food restriction gene therapy human IRS2 protein inhibitor/antagonist insulin receptor substrate 1 protein kinase inhibitor leptin receptor obesity treatment oxidation prevent programs promoter receptor receptor expression research study response senescence transcription factor vector

项目摘要

Obesity is the most prevalent nutritional disorder in Western societies. More than three in ten adult Americans weigh at least 20% in excess of their ideal body weight. Increased body weight is an important public health problem because it is associated with type II diabetes, hypertension and hyperlipidemia. Moreover, adults tend to gain weight, as they get older. Our data suggests that the F-344/BN rat is a reasonable model for age-related obesity in humans. These rats demonstrate a steady increase in body fat into early senescence similar to what occurs in humans. Most obese animal models, whether associated with genetic, diet-induced or age-related obesity, display pronounced leptin resistance, rendering leptin treatment futile in treating obesity. We discovered that aged rats display central leptin resistance characterized by reduced hypothalamic leptin receptors and diminished STAT3 signaling, and that elevated central leptin due to recombinant adeno-associated virus (rAAV) leptin gene delivery induces a leptin resistance in rats of various ages. Elevated central leptin and reduced leptin receptor expression/numbers appear to be common to all models of leptin resistance. Our central hypothesis focuses on two aspects of the leptin signal cascade: (1) diminished leptin signaling associated with elevated central leptin, in particular reduced activity of the leptin-activated insulin receptor substrate (IRS)-mediated phosphatidylinositol-3-OH kinase (PI3K) pathway constitutes one component of age-related or leptin-induced leptin resistance; and (2) elevated central leptin with age contributes to diminished leptin signaling and leptin resistance independent of obesity. We will test our hypotheses by examining (1) whether the leptin activated IRS-PI3K signaling pathway is impaired with age and with leptin-induced leptin resistance; (2) whether inhibition of the IRS-PI3K component of leptin signaling facilitates the development of leptin resistance; and if elevated central leptin with age is the primary factor in impaired leptin signaling and leptin resistance independent of obesity. Understanding the nature of the leptin resistance is paramount to combating obesity, for only then can we fully exploit the potency of leptin in otherwise leptin-resistant rodents or humans. Such discoveries may lead to new treatments for obesity and the diabetes associated with obesity.

肥胖是西方社会最普遍的营养失调。超过十分之三的美国成年人体重比理想体重至少高出20%。体重增加是一个重要的公共卫生问题，因为它与II型糖尿病、高血压和高脂血症有关。此外，随着年龄的增长，成年人的体重往往会增加。我们的数据表明，F-344/BN大鼠是人类年龄相关肥胖的合理模型。这些大鼠的身体脂肪稳步增加，进入早期衰老，这与人类的情况相似。大多数肥胖动物模型，无论是与遗传、饮食诱导还是与年龄相关的肥胖，都表现出明显的瘦素抵抗，使得瘦素治疗对肥胖无效。我们发现，老年大鼠表现出中枢性瘦素抵抗，其特征是下丘脑瘦素受体减少和STAT3信号减少，并升高

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Region-specific diet-induced and leptin-induced cellular leptin resistance includes the ventral tegmental area in rats.

DOI：
10.1016/j.neuropharm.2010.11.002
发表时间：
2011-02
期刊：
NEUROPHARMACOLOGY
影响因子：
4.7
作者：
Matheny, M.;Shapiro, A.;Tuemer, N.;Scarpace, P. J.
通讯作者：
Scarpace, P. J.

The act of voluntary wheel running reverses dietary hyperphagia and increases leptin signaling in ventral tegmental area of aged obese rats.

自愿跑轮的行为可以逆转老年肥胖大鼠的饮食过量并增加腹侧被盖区的瘦素信号传导。

DOI：
10.1159/000321343
发表时间：
2011
期刊：
Gerontology
影响因子：
3.5
作者：
Shapiro,Alexandra;Cheng,Kit-Yan;Gao,Yongxin;Seo,Dong-Oh;Anton,Steve;Carter,ChristyS;Zhang,Yi;Tumer,Nihal;Scarpace,PhilipJ
通讯作者：
Scarpace,PhilipJ

Pro-opiomelanocortin gene transfer to the nucleus of the solitary track but not arcuate nucleus ameliorates chronic diet-induced obesity.

DOI：
10.1016/j.neuroscience.2010.06.001
发表时间：
2010-09-15
期刊：
NEUROSCIENCE
影响因子：
3.3
作者：
Zhang, Y.;Rodrigues, E.;Gao, Y. X.;King, M.;Cheng, K. Y.;Erdos, B.;Tumer, N.;Carter, C.;Scarpace, P. J.
通讯作者：
Scarpace, P. J.

Leptin overexpression in VTA trans-activates the hypothalamus whereas prolonged leptin action in either region cross-desensitizes.