title: Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5.
abstract: Obesity induced in mice by high-fat feeding activates the protein kinase Cdk5 (cyclin-dependent kinase 5) in adipose tissues. This results in phosphorylation of the nuclear receptor PPARgamma (peroxisome proliferator-activated receptor gamma), a dominant regulator of adipogenesis and fat cell gene expression, at serine 273. This modification of PPARgamma does not alter its adipogenic capacity, but leads to dysregulation of a large number of genes whose expression is altered in obesity, including a reduction in the expression of the insulin-sensitizing adipokine, adiponectin. The phosphorylation of PPARgamma by Cdk5 is blocked by anti-diabetic PPARgamma ligands, such as rosiglitazone and MRL24. This inhibition works both in vivo and in vitro, and is completely independent of classical receptor transcriptional agonism. Similarly, inhibition of PPARgamma phosphorylation in obese patients by rosiglitazone is very tightly associated with the anti-diabetic effects of this drug. All these findings strongly suggest that Cdk5-mediated phosphorylation of PPARgamma may be involved in the pathogenesis of insulin-resistance, and present an opportunity for development of an improved generation of anti-diabetic drugs through PPARgamma.
authors.affiliation: Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Jang Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Banks
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Estall
authors.forename: Shingo
authors.initials: S
authors.lastname: Kajimura
authors.forename: Pontus
authors.initials: P
authors.lastname: Boström
authors.forename: Dina
authors.initials: D
authors.lastname: Laznik
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Ruas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chalmers
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009765:Obesity / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011487:Protein Conformation; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D004041:Dietary Fats; D007328:Insulin; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D010768:Phosphoserine; D051360:Cyclin-Dependent Kinase 5