Age-related Obesity: Interventions with Gene Delivery

描述（由申请人提供）：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超过理想体重至少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，成年人随着年龄的增长，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性肥胖的合理模型。这些大鼠表现出体内脂肪的稳定增加，进入早期衰老，类似于人类中发生的情况。大多数肥胖动物模型，无论是与遗传、饮食诱导还是年龄相关的肥胖相关，都显示出明显的瘦素抵抗，使得瘦素治疗在治疗肥胖中无效。使用重组腺相关病毒（rAAV）作为长期瘦素基因递送的载体，我们的数据表明，瘦素，肥胖和年龄都有助于瘦素抵抗。此外，我们的数据表明，瘦素不能激活黑皮质素（MC）通路，和MC激动剂是有效的，在老年瘦素抵抗大鼠。我们的中心假设是，受损的MC通路的激活，其特征在于减少MC张力的基础瘦素抵抗的机制之一。我们将研究瘦素信号转导的大鼠瘦素抵抗无论是慢性瘦素治疗或年龄相关性肥胖，这是否会导致减少MC的张力，并试图绕过瘦素抵抗的gent交付rAAV-POMC，基因编码的cx-MSH的前体肽。具体来说，这项建议旨在解决三个问题，在大鼠的三个年龄：瘦素诱导的或年龄诱导的瘦素抵抗是否导致减少黑皮质素紧张。沉默rAAV-传递的瘦素转基因是否会逆转下调的瘦素信号传导并恢复黑皮质素张力？用rAAVPOMC治疗将规避瘦素抗性并减少瘦素抗性大鼠中的肥胖。了解瘦素抵抗的本质对于对抗肥胖至关重要，因为只有这样我们才能充分利用瘦素在其他瘦素抵抗的啮齿动物或人类中的效力。这些发现可能会导致肥胖症和与肥胖相关的糖尿病的新疗法。

DESCRIPTION (provided by applicant): Obesity is the most prevalent nutritional disorder in Western societies. More than three in ten adult Americans weigh at least 20 percent 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. Using recombinant adeno-associated virus (rAAV) as a vehicle for long-term leptin gene delivery, our data indicate that leptin, obesity, and age all contribute to the leptin resistance. Furthermore, our data indicate that leptin fails to activate the melanocortin (MC) pathway, and MC agonists are effective in aged-leptin-resistant rats. Our central hypothesis is that impaired activation of the MC pathway characterized by diminished MC tone underlies one mechanism of leptin resistance. We will examine leptin signal transduction in rats made leptin resistant by either chronic leptin treatment or agerelated obesity, whether this results in diminished MC tone, and attempt to circumvent the leptin resistance by gent delivery of rAAV-POMC, the gene coding for the precursor peptide of cx-MSH. Specifically, this proposal seeks to address three questions in rats of three ages: Does leptin-induced or age-induced leptin resistance result from diminished melanocortin tone. Will silencing of the rAAV-delivered leptin transgene reverse the down-regulated leptin signaling and restore melanocortin tone? Will treatment with rAAVPOMC circumvent leptin resistance and reduce adiposity in leptin resistant rats. 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.