The related conditions, obesity and diabetes are receiving a considerable level of drug development attention and one pharmacological target that has been in the spotlight for both is leptin. 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, and hence a considerable amount of research is being conducted to determine the mechanism of action of leptin. Recent reports have suggested that the movement of leptin across the blood-brain barrier is defective in obese patients, while even more recently (see "The best of the rest" section of this edition of TherapeuticAdvances) it has been shown that protein tyrosine phosphatase 1B (PTP-1B) is able to block the response to leptin receptor binding. This finding is particularly interesting since PTP-1B activity is increased in obese individuals and this enzyme has already been shown to down-regulate insulin signalling. As a result of these earlier studies PTB-1B inhibitors are being developed by the pharmaceutical sector, however the new finding that PTB-1B modulates leptin activity suggests that such inhibitors may enjoy a synergistic relationship with leptin agonists. Interest in leptin activity which is not directly related to obesity or diabetes has also grown. Three new publications have been added to "The best of the rest" section of TherapeuticAdvances this week alone. One area to have received much attention is bone growth. The evidence so far indicates that leptin controls bone growth in two ways. It stimulates the release of hypothalamic osteoblast-inhibiting factor(s), which limit(s) the amount of bone matrix that osteoblasts can make. Interestingly, leptin is itself a bone anabolic factor that directly stimulates bone growth by inducing osteoblasts to make insulin-like growth factor-I and inhibiting osteoclast generation. Leptin receptors have also been identified on breast cancer cells and their activation has been shown to stimulate proliferation suggesting that leptin may contribute to the progression of breast cancer. Similar suggestions have been made for prostate and colon cancer. Finally, leptin also appears to play an important role in inflammation, and more specifically leptin appears to worsen inflammation in models of inflammatory bowel disease (IBD) and multiple sclerosis while on the other hand it increases survival in models of sepsis. Conversely, leptin deficiency protects against inflammation in animal models of IBD and arthritis while it increases sepsis-related mortality. Thus the field of leptin is rapidly evolving and strategies for conferring therapeutic activity to this mediator are now becoming clearer, not only for use in obese and diabetic patients but also in patients with sepsis or osteoporosis. On the other hand leptin treatment has the potential to exacerbate a variety of inflammatory conditions. This suggests that care should be taken in the development of leptin receptor agonists, however, more positively, it also raises the possibility of developing leptin receptor antagonists for use in a number of serious and debilitating diseases

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