It is estimated that somewhere between 34 and 61 million people in the US are obese. Likewise in much of the developing world obesity represents a massive and growing problem. As a general guide, obesity increases the likelihood of death from all causes by 20%. High levels of serum triglyceride are also related to the development of insulin resistance and diabetes. Following the withdrawal of early treatments, the market for anti-obesity pharmaceuticals was reestablished in November 1997, when the FDA approved Abbott's sibutramine (Reductil/Meridia), for use in obesity, and still further in April 1999, when Roche's Xenical (orlistat) was also approved. The world obesity market has been predicted to reach $3.7 billion by 2008 with a compound annual growth rate of 21.1%. This market potential has caused pharmaceutical companies to prioritize the identification of novel anti-obesity products and consequently the number of drugs in development has risen 3-fold over the past 7 years largely due to an increase in preclinical research activities. Pharmaceutical classes receiving greatest attention include 5-HT modulating drugs; beta 3 adrenoreceptor agonists; lipase inhibitors; melanocortin 4 agonists; and leptin agonists. Leptin agonists have created a storm of interest since this mediator is able to reduce feeding however recent observations that obese individuals produce high levels of and are resistant to leptin has driven the search for alternatives. Ghrelin represents one particularly promising breaking targets in the field of obesity prompting LeadDiscovery to produce a DiscoveryDossier analyzing this field. More recently, Harvard researchers have published breakthrough data concerning c-Jun N-terminal kinase (JNK). A little over a year ago LeadDiscovery overviewed therapeutic targets related to the development of insulin resistance including TNF-alpha. TNF-alpha has been shown to activate JNK, which has been reported to directly phosphorylate ser-307 and hence inactivate IRS1 causing insulin resistance. The Harvard group now shows that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signaling capacity in two different models of mouse obesity. Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics. To date a limited number of JNK inhibitors have been developed but as of yet they have not been indicated for obesity, insulin resistance or associated conditions.

Entry date January 2003

Adapted from Hirosumi et al, Nature 2002 Nov 21;420(6913):333-6 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.