The promise of ghrelin antagonism in obesity treatment

Abstract

According to the World Health Organization, 300 million people are clinically obese worldwide. As a major risk factor in the development of life-threatening diseases such as diabetes, cardiovascular disease and certain cancers, obesity is quickly evolving into a serious public health threat on a global scale. This alarming situation calls for the development of effective treatments, including pharmacological intervention. Many biotechnology and pharmaceutical companies have embarked on the endeavor to develop safe new therapeutics for weight loss and durable weight management. Much progress has been made to improve our understanding of the regulation of energy homeostasis, but this knowledge has not yet translated into new medicines. However, it has led to the identification of molecules that promise to be highly interesting targets for therapeutic intervention. One such molecule is the enteric hormone ghrelin. Ghrelin was identified in 1999 as the endogenous ligand for the growth hormone secretagogue-receptor 1a (GHS-R1a). Soon after its discovery ghrelin was shown to increase food intake, downregulate energy expenditure and conserve body fat, causing weight gain and adipogenesis. Unsurprisingly, these findings placed ghrelin and its receptor on the radar screens of many medical researchers in academia and the pharmaceutical industry. The resulting attention has led to a steadily growing body of evidence in support of ghrelin antagonism as a potential means to ameliorate obesity. But the causes for obesity are manifold, and skepticism about the utility of this approach remains. The current review summarizes the arguments for and against ghrelin as a potential antiobesity target and discusses recent pharmaceutical developments to interfere with this exciting pathway.