Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5.

Nature
Jang Hyun ChoiBruce M Spiegelman

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.

References

Jul 24, 1987·Science·J S FlierB M Spiegelman
May 3, 1996·The Journal of Biological Chemistry·E HuB M Spiegelman
Aug 1, 1996·Human Gene Therapy·T M Kinsella, G P Nolan
Dec 1, 1996·Nature Biotechnology·D J LockhartE L Brown
Jan 4, 2001·The Journal of Nutrition·R F Morrison, S R Farmer
Jan 3, 2001·Proceedings of the National Academy of Sciences of the United States of America·C Li, W H Wong
Feb 24, 2001·Nature·C M SteppanM A Lazar
Apr 11, 2001·Proceedings of the National Academy of Sciences of the United States of America·Y HakakA A Fienberg
Jun 8, 2001·Annual Review of Biochemistry·T M WillsonS A Kliewer
Aug 2, 2001·Nature Medicine·A H BergP E Scherer
Oct 5, 2001·Nature Reviews. Molecular Cell Biology·R Dhavan, L H Tsai
Jan 10, 2002·Genes & Development·Evan D RosenBruce M Spiegelman
Apr 25, 2003·The New England Journal of Medicine·Eugenia E CalleMichael J Thun
Jun 8, 2004·The Journal of Clinical Endocrinology and Metabolism·Erin E Kershaw, Jeffrey S Flier
Dec 18, 2004·Bioorganic & Medicinal Chemistry Letters·John J ActonHarold B Wood
May 3, 2005·BMJ : British Medical Journal·Rachel A WhitmerKristine Yaffe
Jun 7, 2005·Prostaglandins, Leukotrienes, and Essential Fatty Acids·S Cinti
Jan 13, 2006·Methods in Enzymology·Claudia S Maier, Max L Deinzer
Oct 24, 2006·Endocrine Reviews·Maria E Trujillo, Philipp E Scherer
Oct 25, 2006·Molecular and Cellular Biology·Maria A JimenezEvan D Rosen
Oct 17, 2007·Structure·John B BruningPatrick R Griffin
Dec 13, 2007·JAMA : the Journal of the American Medical Association·Lorraine L LipscombeDavid A Alter
Jul 16, 2008·The Journal of Biological Chemistry·Christopher J Walkey, Bruce M Spiegelman
Oct 17, 2009·Diabetes·José María Moreno-NavarreteJosé Manuel Fernández-Real

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Citations

May 29, 2013·International Journal of Obesity : Journal of the International Association for the Study of Obesity·X LiT Park
Jun 22, 2011·Journal of Computer-aided Molecular Design·Laura GuaschSantiago Garcia-Vallvé
Jul 14, 2012·Current Neurology and Neuroscience Reports·Jill K Morris, Jeffrey M Burns
Oct 13, 2011·Chemical Reviews·Gregory S HarmonChristopher K Glass
Nov 8, 2012·Journal of Medicinal Chemistry·Estel la BuscatóEwgenij Proschak
Jul 24, 2010·Nature·Riekelt H Houtkooper, Johan Auwerx
Mar 15, 2013·Nature·Vikas ChandraFraydoon Rastinejad
May 9, 2013·Nature Medicine·Maryam AhmadianRonald M Evans
Oct 9, 2013·Nature Medicine·Matthew Harms, Patrick Seale
Sep 3, 2010·Nature Reviews. Drug Discovery·Dan Jones
Sep 1, 2012·Nature Reviews. Drug Discovery·Roberto Coppari, Christian Bjørbæk
May 15, 2013·Nature Reviews. Drug Discovery·Pénélope A AndreuxJohan Auwerx
Apr 12, 2011·Nature Structural & Molecular Biology·Jun ZhangPatrick R Griffin
Dec 31, 2010·The New England Journal of Medicine·Barbara B Kahn, Timothy E McGraw
Apr 18, 2012·Proceedings of the National Academy of Sciences of the United States of America·Christopher WeidnerSascha Sauer
Jan 30, 2013·Proceedings of the National Academy of Sciences of the United States of America·Ann HammarstedtUlf Smith
Mar 21, 2013·Proceedings of the National Academy of Sciences of the United States of America·Ajit S DivakaruniAnne N Murphy
Aug 5, 2011·The Journal of Biological Chemistry·Atsushi NoharaMasatomo Mori
May 16, 2012·The Journal of Biological Chemistry·Angélica A AmatoFrancisco A R Neves
Jun 8, 2011·Genes & Development·Yaniv LustigBruce M Spiegelman
Jan 12, 2013·Science·Ira Tabas, Christopher K Glass
Oct 21, 2010·American Journal of Physiology. Endocrinology and Metabolism·Kevin E YarasheskiDominic N Reeds
Jan 27, 2012·American Journal of Physiology. Renal Physiology·Eric T WeatherfordCurt D Sigmund
Nov 13, 2010·Journal of Applied Physiology·Marilyn J CipollaSiu-Lung Chan
Oct 27, 2011·International Journal of Endocrinology·Danish Ahmed, Manju Sharma
Sep 12, 2012·PPAR Research·Gene P Ables
Jun 30, 2012·PPAR Research·Angélica Amorim Amato, Francisco de Assis Rocha Neves
Apr 12, 2013·BMC Medical Informatics and Decision Making·Woochang HwangDoheon Lee
Oct 30, 2012·Diabetology & Metabolic Syndrome·Bodo HaasNiels Eckstein
Jun 12, 2012·Journal of Lipid Research·Janice V HuangGregory G Schwartz

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Methods Mentioned

BETA
biopsies
PCR
ELISA
immunoprecipitation
transfection
DNA-Chip

Software Mentioned

SPSS
Affymetrix

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