Update on melanocortin interventions for cachexia: progress toward clinical application

Abstract

Cachexia is a devastating syndrome of body wasting that is associated with multiple common chronic diseases including cancer, chronic kidney disease, and chronic heart failure. These underlying diseases are associated with increased levels of inflammatory cytokines and result in anorexia, increased resting energy expenditure, and loss of fat and lean body mass. Prior experiments have implicated the central melanocortin system in the hypothalamus with the propagation of these symptoms of cachexia. Pharmacologic blockade of this system using melanocortin antagonists causes attenuation of the signs of cachexia in laboratory models. Recent advances in our knowledge of this disease process have involved further elucidation of the pathophysiology of melanocortin activation and demonstration of the efficacy of melanocortin antagonists in new models of cachexia, including cardiac cachexia. In addition, small molecule antagonists of the melanocortin-4 receptor continue to be introduced, including ones with oral bioavailability. These developments generate optimism that melanocortin antagonism will be used to treat humans with disease-associated cachexia. However, to date, human application has remained elusive and it is unclear when we will know whether humans with cachexia would benefit from treatment with these compounds.

Figure 1. Model for activation of the central melanocortin system in the hypothalamus during cachexia

The melanocortin system is comprised of neurons expressing either POMC or AgRP, each or which express receptors to IL-1β. During cachexia inflammatory cytokines are released; IL-1β acts on the IL1-RI to increase release of a-MSH from POMC neurons and decrease release of AgRP. This causes an increase in activity at the melanocortin-4 receptors (MC4R) at second order neurons and downstream events characteristic of cachexia. Blockade of this signal by melanocortin antagonists attenuates these downstream events. Additionally, increased production of AgRP, as is caused by the effect of ghrelin at the GHS-1 receptor, also blocks melanocortin output. (Figure adapted from reference [50], used by permission.)