Dexamethasone-mediated changes in adipose triacylglycerol metabolism are exaggerated, not diminished, in the absence of a functional GR dimerization domain.
The glucocorticoid (GC) receptor (GR) has multiple effector mechanisms, including dimerization-mediated transactivation of target genes via DNA binding and transcriptional repression mediated by protein-protein interactions. Much attention has been focused on developing selective GR modulators that would dissociate adverse effects from therapeutic anti-inflammatory effects. The GR(dim/dim) mouse has a mutation in the dimerization domain of GR and has been shown to have attenuated transactivation with intact repression. To understand the role of GR dimerization-dependent targets in multiple tissues, we measured metabolic fluxes through several disease-relevant GC target pathways using heavy water labeling and mass spectrometry in wild-type and GR(dim/dim) mice administered the potent GC dexamethasone (DEX). Absolute triglyceride synthesis was increased in both wild-type and GR(dim/dim) mice by DEX in the inguinal and epididymal fat depots. GR(dim/dim) mice showed an exaggerated response to DEX in both depots. De novo lipogenesis was also greatly increased in both depots in response to DEX in GR(dim/dim), but not wild-type mice. In contrast, the inhibitory effect of DEX on bone and skin collagen synthesis rates was greater in wild-type compared with GR(dim/dim) mice. Wild-type mice were more sensitive to DEX-dependent decreases in insulin sensitivity than GR(dim/dim) mice. Wild-type and GR(dim/dim) mice were equally sensitive to DEX-dependent decreases in muscle protein synthesis. Chronic elevation of GCs in GR(dim/dim) mice results in severe runting and lethality. In conclusion, some metabolic effects of GC treatment are exaggerated in adipose tissue of GR(dim/dim) mice, suggesting that selective GR modulators based on dissociating GR transactivation from repression should be evaluated carefully.
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CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
Dexamethasone triacylglycerol GR GR insulin GR GR GR GR GR DEX GR GR GR GR glucocorticoid (GC) receptor GR GR GR GR GR DEX GR dimerization domain DEX DEX DEX dexamethasone DEX triglyceride DEX