Endocrine Abstracts

Endogenous glucocorticoids help to mobilize energy to prepare for daily activity and to deal with stressors, e.g. by catabolic effects on muscle and stimulation of the release of glucose and fat from the liver. Chronic overexposure to glucocorticoids has strong deleterious effects, in medical glucocorticoid and in Cushing’s disease. It is less clear to what extent glucocorticoid signalling may be used as a therapeutic target in the much more frequent consequences of the metabolic syndrome. We have tested new GR antagonists and selective GR modulators in mouse models of metabolic syndrome. Selective modulators combine antagonism on some GR-mediated processes with (partial) agonism on others. In a series of experiments, we have found that selective receptor modulation can have pronounced benefits over full antagonism in these models. E.g. some level of anti-inflammatory efficacy may be beneficial. Selective GR modulator C118335 in mice had very pronounced effects on hepatic liver accumulation. Due to its GR agonism on VLDL production, but lack of agonism on lipid uptake by the liver, this compound can fully prevent and reverse hepatic liver accumulation in mice after 6 weeks on high fat diet. These data suggest that the glucocorticoid receptor is a valid target, and that selective modulation, by interfering with GR-stimulated metabolic fluxes, may have advantages over full antagonism of the GR.