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.
