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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020985-04
Application #
7106641
Study Section
Geriatrics and Rehabilitation Medicine (GRM)
Program Officer
Finkelstein, David B
Project Start
2003-09-01
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2008-08-31
Support Year
4
Fiscal Year
2006
Total Cost
$330,180
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Zhang, Yi; Rodrigues, Enda; Li, Gang et al. (2011) Simultaneous POMC gene transfer to hypothalamus and brainstem increases physical activity, lipolysis and reduces adult-onset obesity. Eur J Neurosci 33:1541-50
Zhang, Yi; Collazo, Renata; Gao, Yongxin et al. (2010) Intermittent MTII application evokes repeated anorexia and robust fat and weight loss. Peptides 31:639-43
Judge, M K; Zhang, J; Tumer, N et al. (2008) Prolonged hyperphagia with high-fat feeding contributes to exacerbated weight gain in rats with adult-onset obesity. Am J Physiol Regul Integr Comp Physiol 295:R773-80
Tumer, Nihal; Erdos, Benedek; Matheny, Michael et al. (2007) Leptin antagonist reverses hypertension caused by leptin overexpression, but fails to normalize obesity-related hypertension. J Hypertens 25:2471-8
Li, G; Zhang, Y; Cheng, K Y et al. (2007) Lean rats with hypothalamic pro-opiomelanocortin overexpression exhibit greater diet-induced obesity and impaired central melanocortin responsiveness. Diabetologia 50:1490-9
Li, Gang; Zhang, Yi; Rodrigues, Enda et al. (2007) Melanocortin activation of nucleus of the solitary tract avoids anorectic tachyphylaxis and induces prolonged weight loss. Am J Physiol Endocrinol Metab 293:E252-8
Zhang, J; Matheny, M K; Tumer, N et al. (2007) Leptin antagonist reveals that the normalization of caloric intake and the thermic effect of food after high-fat feeding are leptin dependent. Am J Physiol Regul Integr Comp Physiol 292:R868-74
Scarpace, Philip J; Matheny, Michael; Zhang, Yi et al. (2007) Leptin antagonist reveals an uncoupling between leptin receptor signal transducer and activator of transcription 3 signaling and metabolic responses with central leptin resistance. J Pharmacol Exp Ther 320:706-12
Li, G; Zhang, Y; Wilsey, J T et al. (2005) Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats. Diabetologia 48:2376-85