AMPK Regulates Metabolic Actions of Glucocorticoids by Phosphorylating the Glucocorticoid Receptor through p38 MAPK

Abstract

Glucocorticoids play central roles in the regulation of energy metabolism by shifting it toward catabolism, whereas AMP-activated protein kinase (AMPK) is the master regulator of energy homeostasis, sensing energy depletion and stimulating pathways of increasing fuel uptake and saving on peripheral supplies. We showed here that AMPK regulates glucocorticoid actions on carbohydrate metabolism by targeting the glucocorticoid receptor (GR) and modifying transcription of glucocorticoid-responsive genes in a tissue- and promoter-specific fashion. Activation of AMPK in rats reversed glucocorticoid-induced hepatic steatosis and suppressed glucocorticoid-mediated stimulation of glucose metabolism. Transcriptomic analysis in the liver suggested marked overlaps between the AMPK and glucocorticoid signaling pathways directed mostly from AMPK to glucocorticoid actions. AMPK accomplishes this by phosphorylating serine 211 of the human GR indirectly through phosphorylation and consequent activation of p38 MAPK and by altering attraction of transcriptional coregulators to DNA-bound GR. In human peripheral mononuclear cells, AMPK mRNA expression positively correlated with that of glucocorticoid-responsive glucocorticoid-inducible leucine zipper protein, which correlated also positively with the body mass index of subjects. These results indicate that the AMPK-mediated energy control system modulates glucocorticoid action at target tissues. Because increased action of glucocorticoids is associated with the development of metabolic disorders, activation of AMPK could be a promising target for developing pharmacological interventions to these pathologies.

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

“…Our observation that p38 MAPK regulates GR phosphorylation at S203 combined with the fact that in other cell types p38 MAPK also phosphorylates GR at S211 (13,46) suggests that this kinase can affect GR function by acting on multiple serine residues. In line with this, we showed that p38 MAPK can suppress GR function by exerting two opposite actions on GR key serine residues, namely directly phosphorylating S203 and interfering with GR phosphorylation at S211.…”

Glucocorticoid hormones and energy homeostasis

“…Smad6 suppresses GR-induced transactivation by attracting HDAC3 to DNA-bound GR and by antagonizing acetylation of histone H3 and H4 induced by p160/SRC1 [64]. In addition, AMP-activated kinase (AMPK) counteracts GC/GR-induced upregulation of the gluconeogenic program in liver by specifically phosphorylating the GR at serine 211 and releasing p300 and the SWF/SNF chromatin remodelling complex component SNF2 from gluconeogenic GR target gene promoters [65], suggesting that AMPK may directly link cellular energy status to systemic Bereitgestellt von | Uppsala University Library Angemeldet Heruntergeladen am | 17.11.14 12:00 glucose homeostasis through the control of GR-associated transcriptional co-factor complexes in the liver.…”

Minireview: New Molecular Mediators of Glucocorticoid Receptor Activity in Metabolic Tissues

“…SMAD6 suppresses GR-mediated transactivation by attracting histone deacetylase 3 (HDAC3) to DNAbound GR and subsequently, antagonizing acetylation of histone H3 and H4 induced by SRC-1 (63). In another unique mechanism, Nadar et al (2010) recently found that phosphorylation of GR at serine 232 by MAPK p38 can discharge p300 and the SWF/SNF chromatin remodelling complex component SNF2 from gluconeogenic GR bound promoters in rat liver (64). Since AMP-activated kinase (AMPK) activates MAPK p38, this provides a mechanism by which the organism 'senses' its low energy status and turns-off ATP-consuming metabolic programs including gluconeogenesis (65).…”

“…Since AMP-activated kinase (AMPK) activates MAPK p38, this provides a mechanism by which the organism 'senses' its low energy status and turns-off ATP-consuming metabolic programs including gluconeogenesis (65). Indeed, when rats were treated with the AMPK activator AICAR, Dex-induced hepatic steatosis and gluconeogenesis were attenuated (64).…”