title: 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.
authors.affiliation: Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Clinical Research Center, Room 1-3140, 10 Center Drive MSC 1109, Bethesda, MD 20892-1109, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Nader
authors.forename: Sinnie Sin Man
authors.initials: SS
authors.lastname: Ng
authors.forename: George I
authors.initials: GI
authors.lastname: Lambrou
authors.forename: Panagiota
authors.initials: P
authors.lastname: Pervanidou
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wang
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D015992:Body Mass Index; D020134:Catalytic Domain; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005234:Fatty Liver / Q000097:blood / Q000201:enzymology / Q000473:pathology; D055785:Gene Knockdown Techniques; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D012265:Ribonucleotides; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D010768:Phosphoserine; D000620:Aminoimidazole Carboxamide; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide