The identification of new targets for obesity therapeutics represents a key priority for the pharmaceutical industry. This has been driven by the large and growing numbers of obese individuals around the world, the high incidence of serious co-morbidities, and a market predicted to reach $3.7 billion by 2008.

Obesity occurs when calorific intake exceeds energy expenditure. LeadDiscovery has recently analyzed two emerging anti-obesity targets, ghrelin which regulates food intake , and the retinoids which also plays a role in both food intake as well as energy expenditure .

Leptin has received considerable interest with respect to obesity. Leptin is released into the blood from fat cells and circulates to the brain where it crosses the blood-brain barrier to act at receptors within the central nervous system. Leptin inhibits food intake, reduces body weight and stimulates energy expenditure. Leptin expression increases after food intake and decreases during fasting. Reduced expression has been shown to evoke insulin resistance, while a leptin agonist has recently been shown to not only reduce body weight and glucose levels in obese animals but also to increase insulin sensitivity. Despite the promise that leptin agonists may have for the treatment of both diabetes and obesity, such molecules have only met with limited success in clinical trials. This lack of effect has been suggested to result from the development of leptin resistance. Various different mechanisms of leptin resistance have been proposed including a defect in the transport of leptin across the blood-brain barrier. This suggests that strategies that may increase hypothalmic leptin expression may overcome resistance and hence reduce obesity. University of Florida researchers have recently tested this hypothesis by using viral vectors to introduce the leptin gene into the brain. A single injection of recombinant adeno-associated virus encoding the leptin gene (rAAV-lep) into the third cerebroventricle prevented aging-associated increase in body weight and adiposity in adult rats for 6 months of the experiment. In addition, obesity was prevented in rats introduced to a high-fat diet and also reversed in obese-prone rats maintained on a high-fat diet. Body weight homeostasis and loss of adiposity by leptin gene therapy was achieved by an increase in energy expenditure, and when the rAAV-lep titer was increased, there was also a voluntary reduction in food intake. Importantly, this therapy reduced blood levels of insulin, triglycerides and free fatty acids, the pathophysiologic correlates of the metabolic syndrome. Thus, the long-term beneficial effects of central leptin gene therapy may herald the development of newer therapeutic strategies to control the epidemic of obesity and related metabolic disorders.

Entry date March, 2003

Adapted from Kalra & Kalra, Drugs Today (Barc) 2002 Nov;38(11):745-57 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk