Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5.
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.
Choi
Jang Hyun
JH
Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Banks
Alexander S
AS
Estall
Jennifer L
JL
Kajimura
Shingo
S
Boström
Pontus
P
Laznik
Dina
D
Ruas
Jorge L
JL
Chalmers
Michael J
MJ
Kamenecka
Theodore M
TM
Blüher
Matthias
M
Griffin
Patrick R
PR
Spiegelman
Bruce M
BM
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
D004041:Dietary Fats; D007328:Insulin; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D010768:Phosphoserine; D051360:Cyclin-Dependent Kinase 5