Obesity represents a global problem with high associated mortality and co-morbidities, and the world obesity market has been predicted to reach $3.7 billion by 2008. The drive to develop new treatments for obesity is therefore immense. Ghrelin represents one particularly promising breaking targets in the field of obesity prompting LeadDiscovery to produce a DiscoveryDossier analyzing this field.

Many of the problems related to obesity are due to the development of insulin resistance and diabetes and the development of agents able to both reverse insulin resistance and reduce body weight may be particularly beneficial. The peroxisome proliferator-activated nuclear receptor (PPAR) family has received particular scrutiny and as a result the thiazolidinediones have emerged as a therapeutic class for the treatment of diabetes. First generation thiazolidinediones were agonists of the PPARgamma receptor and were able to reduce insulin resistance. One adverse effect associated with PPARgamma receptor agonists is however weight gain. Given the comorbidity of type II diabetes and obesity this can limit the usefulness of such molecules. Quite unexpectedly, a moderate reduction of PPARgamma activity observed in heterozygous PPARgamma-deficient mice, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. Consequently PPARgamma antagonists are now being developed.

More recently molecules have been developed that activate PPARalpha. This class is able to reduce triglyceride levels and is also able to improve insulin sensitivity and as a result dual PPARalpha/PPARgamma agonists have been developed with proposed beneficial effects over existing PPARgamma- and alpha-preferential drugs, respectively, in treatment of type 2 diabetes.

PPAR receptors exist as heterodimers along with the retinoid X receptor (RXR) and like the PPARs, the retinoids have also been attracting considerable attention due to their potential to regulate metabolic imbalance as well as the proliferation of cancer cells. This field has been the subject of a recent DiscoveryDossier (click here for access). Of particular interest Ligand Pharmaceuticals have recently developed a RXR:PPARgamma ligand.

Given the potential role of RXR ligands in the treatment of metabolic disease UCLA researchers have recently investigated the effects of RXRalpha gene deletion on various metabolic parameters. Hepatocyte RXRalpha-deficient mice fed a high-saturated-fat diet were found to have increased leptin levels. This was related to reduced food intake and improved glucose tolerance suggesting that RXRalpha antagonists may confer therapeutic advantage in obese diabetes. Improved glucose tolerance was related to increased IGF-I levels. Unfortunately, body weight and fat content were significantly higher in these mutant mice due to defective control of fatty acid metabolism and a compromised PPARalpha-mediated pathway.

This body of data confirms the ability of RXR antagonists to exert some beneficial effects in metabolic disorders increasing energy consumption, reducing food intake and improving glucose tolerance. On the other hand deleting the RXR receptor promotes obesity. Since RXR forms heterodimers with both PPARalpha and PPARgamma blocking RXR may produce a phenotype that shares some similarities with PPARalpha deletion and others with PPARgamma deletion. Since therapeutic candidates that target PPAR may confer most benefit in the context of diabetes and obesity if they activate PPARalpha and/or block PPARgamma it is conceivable that RXRalpha antagonists may be of use if they are selective for RXR:PPARgamma heterodimers and fail to impede RXR:PPARalpha mediated effects. This is supported in part by recent research showing that the dual antagonism of RXR and PPARgamma decreases triglyceride content, potentiates leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating diet-induced obesity and insulin resistance. Molecules that block RXR:PPARgamma and stimulate RXR:PPARalpha dimers may represent an even better approach.

Entry date March, 2003

Adapted from Wan et al, Endocrinology 2003 Feb;144(2):605-11 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

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