Glucocorticoids regulate numerous processes in human physiology, but deregulated or excessive glucocorticoid receptor (GR) signaling contributes to the development of various pathologies including... Show moreGlucocorticoids regulate numerous processes in human physiology, but deregulated or excessive glucocorticoid receptor (GR) signaling contributes to the development of various pathologies including metabolic syndrome. For this reason, GR antagonists have considerable therapeutic value. Yet, the only GR antagonist that is clinically approved to date - mifepristone - exhibits cross-reactivity with other nuclear steroid receptors like the progesterone receptor. In this study, we set out to identify novel selective GR antagonists by combining rational chemical design with an unbiased in vitro and in vivo screening approach. Using this pipeline, we were able to identify CORT125329 as the compound with the best overall profile from our octahydro series of novel GR antagonists, and demonstrated that CORT125329 does not exhibit cross-reactivity with the progesterone receptor. Further in vivo testing showed beneficial activities of CORT125329 in models for excessive corticosterone exposure and short- and long-term high-fat diet-induced metabolic complications. Upon CORT125329 treatment, most metabolic parameters that deteriorated upon high-fat diet feeding were similarly improved in male and female mice, confirming activity in both sexes. However, some sexually dimorphic effects were observed including male-specific antagonism of GR activity in brown adipose tissue and female-specific lipid lowering activities after short-term CORT125329 treatment. Remarkably, CORT125329 exhibits beneficial metabolic effects despite its lack of GR antagonism in white adipose tissue. Rather, we propose that CORT125329 treatment restores metabolic activity in brown adipose tissue by stimulating lipolysis, mitochondrial activity and thermogenic capacity. In summary, we have identified CORT125329 as a selective GR antagonist with strong beneficial activities in metabolic disease models, paving the way for further clinical investigation. Show less
Ellenbroek, J.H.; Tons, H.A.M.; Meeteren, M.J.A.W. van; Graaf, N. de; Hanegraaf, M.A.; Rabelink, T.J.; ... ; Koning, E.J.P. de 2013
The studies in this thesis are performed to provide additional and improved insight into the effects and interplay of dietary lipids and metabolic inflammation on cardiac performance in the... Show moreThe studies in this thesis are performed to provide additional and improved insight into the effects and interplay of dietary lipids and metabolic inflammation on cardiac performance in the presence or absence of atherosclerosis and myocardial infarctions (MI). We show that high-fat diet feeding has mild but significant detrimental effects on cardiac function. In contrast to our expectations, this effect is not likely to be mediated by Toll-like receptor 2 or Toll-like receptor 4. Also, we demonstrated in mice that high-fat diet feeding does not significantly aggravate cardiac dysfunction post-MI. Deficiency of RP105, a modulator of inflammation, improved cardiac function after induction of MI. In addition, ABCA1 had adverse effects on cardiac function post-MI, possibly via a reduced activation of immune cells. This confirms the important role of inflammation in recovery after MI. Furthermore, we elucidated a possible reason for the failure of niacin in recent clinical trials and found that niacin__s anti-atherogenic properties are most potent by lowering LDL-cholesterol on top of statin treatment. Altogether, these results provide novel insights and targets for the prevention or treatment of cardiovascular diseases. Show less
