Unforeseen role for glucocorticoids in combinatorial anti-obesity pharmacology

In this issue of Molecular Metabolism, Lee et al. report that pharmacological suppression of the hypothalamic-pituitary-adrenal (HPA) e axis, enhances anti-obesity properties of glucagon-like peptide-1 (GLP-1) receptor agonism in obese rats [1]. Whereas previous investigations of the crosstalk between GLP-1 and HPA-axis have illustrated that both central and peripheral administration of GLP-1 analogues promote release of stress-axis hormones, such as ACTH and corticosterone [2,3], the therapeutic potential of this interaction is uncharted. To this end, Lee and colleagues now provide evidence for a novel functional interaction between central incretin action and the endogenous HPA axis in obese rodents. The authors exploit the ability of the synthetic glucocorticoid agent dexamethasone to suppress corticosterone production. They show that blunting endogenous corticosteroid activity by dexamethasone enhances the efficacy of the GLP-1R agonist exendin-4 (Ex-4) to reduce food intake and to lower body weight. Thus, a major conclusion from this article is that the stress-axis may counterbalance the pharmacological benefits of GLP-1 mimetics on energy metabolism. This observation implies potential therapeutic value for treating obesity by inhibiting the stress axis. Indeed, although GLP-1R agonists exert potent gluco-metabolic effects in patients with type-2 diabetes [4], the anti-obesity efficacy of this class of compounds is still dwarfed by the efficacy of the metabolic surgeries [5]. Therefore, identification of pharmacological strategies that can potentiate the metabolic virtues of GLP-1R agonism is a promising undertaking [6]. Frequently reported side effects of dexamethasone and analogous steroid-based glucocorticoids include adiposity and worsened glycemic control [7]. Thus, the use of a glucocorticoid receptor (GR) agonist as a relevant pharmacological partner of GLP-1 mimetics in an antiobesity strategy is somewhat counterintuitive. Irrespective, the report from Lee et al. clearly shows that chronic co-treatment with Ex-4 and dexamethasone synergistically lowers body weight in obese rats [1]. The authors link this finding to the relative low-dose of dexamethasone used, which is believed to scarcely enter the brain, but to exhibit potent endocrine negative feedback at the pituitary to suppress endogenous HPA-activity. Whether this is an accurate explanation for the central sensitization of the metabolic effects of Ex-4 is not completely mapped out in the present study. Nonetheless, GLP-1R activity seems to be