Age-related Obesity: Interventions with Gene Delivery

描述(申请人提供)：肥胖是西方社会最普遍的营养失调。超过三成的美国成年人体重至少超过理想体重的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，成年人的体重往往会随着年龄的增长而增加。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稳步增加，进入早期衰老，类似于人类的情况。大多数肥胖动物模型，无论是与遗传、饮食诱导或年龄相关的肥胖有关，都表现出明显的瘦素抵抗，使瘦素治疗在治疗肥胖症方面无效。使用重组腺相关病毒(RAAV)作为长期传递瘦素基因的载体，我们的数据表明瘦素、肥胖和年龄都与瘦素抵抗有关。此外，我们的数据表明，瘦素不能激活黑素皮质素(MC)途径，MC激动剂对老年瘦素抵抗大鼠有效。我们的中心假设是，以MC张力降低为特征的MC途径的激活受损是瘦素抵抗的一个机制。我们将研究慢性瘦素治疗或年龄相关性肥胖使瘦素抵抗的大鼠的瘦素信号转导，这是否会导致MC张力降低，并试图通过代理传递编码Cx-MSH前体多肽的基因rAAV-POMC来绕过瘦素抵抗。具体地说，这项建议试图解决三个问题：瘦素诱导的瘦素抵抗或年龄诱导的瘦素抵抗是否是由于黑素皮质素张力降低所致。沉默rAAV递送的瘦素转基因会逆转下调的瘦素信号并恢复黑素皮质素的音调吗？RAAVPOMC治疗将绕过瘦素抵抗并减少瘦素抵抗大鼠的肥胖。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，我们才能在其他瘦素抵抗的啮齿动物或人类身上充分发挥瘦素的效力。这些发现可能会为肥胖和与肥胖相关的糖尿病带来新的治疗方法。

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.