title: Dexamethasone-mediated changes in adipose triacylglycerol metabolism are exaggerated, not diminished, in the absence of a functional GR dimerization domain.
abstract: 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.
authors.affiliation: Department of Nutritional Science and Toxicology, University of California Berkeley, Berkeley, California 94720, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Roohk
authors.forename: Smita
authors.initials: S
authors.lastname: Mascharak
authors.forename: Cyrus
authors.initials: C
authors.lastname: Khambatta
authors.forename: Ho
authors.initials: H
authors.lastname: Leung
authors.forename: Marc
authors.initials: M
authors.lastname: Hellerstein
authors.forename: Charles
authors.initials: C
authors.lastname: Harris
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D005938:Glucocorticoids / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D009124:Muscle Proteins; D011965:Receptors, Glucocorticoid; D014280:Triglycerides; D003907:Dexamethasone; D003094:Collagen