LG100268 (LG268) as an appetite suppressor and insulin sensitizing agent

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 (click here for access).

Recent targets for the treatment of obesity as well as other metabolic disorders have emerged from the nuclear receptor familly (for an analysis of nuclear receptors and the key position that they occupy within the pharmaceutical sector, click here). Examples of nuclear receptors can be found in the retinoic acid and the peroxisome proliferator-activated nuclear receptor (PPAR) sub-families. Readers interested in learning more about the development of retinoid ligands and their role in therapeutics may wish to access LeadDiscovery's dossier Retinoids : An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development (click here for access).

Together with its receptor partners, the retinoid X receptor (RXR) has been shown to control numerous key homeostatic pathways. A ubiquitously expressed intracellular receptor, RXR functions as a transcriptional regulator while heterodimerized with other members of the nuclear hormone receptor supergene family. Among the receptors that regulate transcription as obligate heterodimers with RXR are the peroxisome proliferator-activated receptors (the alpha, beta and gamma subtypes), the farnesoid X receptor (FXR) and the liver X receptors (the alpha and beta subtypes). These receptors play major roles in glucose (PPARdelta), triglycerides (PPARalpha), cholesterol (PPARgamma, LXR) and bile acid (FXR) metabolism. In addition to its role in those metabolic pathways, RXR activation has been reported to decreases both body weight gain and food consumption in obese, insulin resistant rodents. In their recent Endocrinology paper Ogilvie et al describe the role that RXR plays in energy balance, investigate the mechanisms underlying these novel activities of RXR pathways, and further characterize Ligand Pharmaceutical’s retinoid receptor agonist, LG100268 (LG268).

Using Zucker fatty rats, this group demonstrated that LG100268 reduced both food intake and body mass gain. This was related to both a reduction meal size and in body fat. Meal size reduction can often cause rebound hyperphagia, and this represents a key limitation to the benefits of using appetite suppressants or food limitation. In the case of LG100268 however, although body weight gain reverted to control levels once LG100268 administration was terminated, meal size remained lower than in controls for 4 days. This lack of rebound hyperphagia satisfies a key criterion for the development of anorectics and resembles data reported for Regeneron Pharmaceuticals’ Axokine, a human recombinant form of CNTF which is showing promise for the treatment of obesity (click here for further information). In contrast to LG100268, the PPARgamma agonist, BRL 49653 increased food intake and body mass gain.

In separate studies, LG100268 increased insulin sensitivity and also serum triglyceride levels. The latter was consistent with a selective increase in adipocyte apoptosis in subcutaneous fat following exposure to LG100268. Further investigation suggested the increase in serum triglyceride levels reflected a peripheral effect while the anorectic activity of LG100268 was central and may reflect binding to retinoid receptors within satiety regions of the hypothalmus.

LG100268 may therefore be of use in obese patients with insulin insensitivity. This is characteristic of obese type II diabetics and hence LG100268 may be of considerable benefit in this growing population. In particular it should be noted that when administered centrally, LG100268 failed to increase triglyceride levels, a potentially adverse effect, and therefore analogues of this molecule that readily penetrate the blood brain barrier deserve further development.

Entry date Tuesday, January 27, 2004

Adapted from Ogilvie et al, Endocrinology. 2003 Nov 6 [Epub ahead of print]