Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation

被引：437

作者：

Choi, Jang Hyun ^{[1
,2
,3
]}

Banks, Alexander S. ^{[1
,2
,3
]}

Kamenecka, Theodore M. ^{[4
,6
]}

Busby, Scott A. ^{[5
]}

Chalmers, Michael J. ^{[5
]}

Kumar, Naresh ^{[5
]}

Kuruvilla, Dana S. ^{[5
]}

Shin, Youseung ^{[4
]}

He, Yuanjun ^{[4
]}

Bruning, John B. ^{[7
]}

Marciano, David P. ^{[5
]}

Cameron, Michael D. ^{[4
,5
,6
]}

Laznik, Dina ^{[1
,2
,3
]}

Jurczak, Michael J. ^{[8
,9
]}

Schuerer, Stephan C. ^{[10
]}

Vidovic, Dusica ^{[10
]}

Shulman, Gerald I. ^{[8
,9
]}

Spiegelman, Bruce M. ^{[1
,2
,3
]}

Griffin, Patrick R. ^{[4
,5
,6
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Metab & Chron Dis, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[4] Scripps Res Inst, Translat Res Inst, Jupiter, FL 33458 USA

[5] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA

[6] Scripps Res Inst, SRMSC, Jupiter, FL 33458 USA

[7] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA

[8] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Internal Med, New Haven, CT 06510 USA

[9] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA

[10] Univ Miami, Ctr Computat Sci, Miami, FL 33136 USA

来源：

NATURE | 2011年 / 477卷 / 7365期

基金：

美国国家卫生研究院;

关键词：

ACTIVATED-RECEPTOR-GAMMA; ADIPOCYTE DIFFERENTIATION; SKELETAL-MUSCLE; ROSIGLITAZONE; EXPRESSION; OBESITY; POTENT; THIAZOLIDINEDIONE; PPAR-GAMMA-2; MODULATORS;

D O I：

10.1038/nature10383

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

PPAR gamma is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone(1). These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPAR gamma-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPAR gamma by Cdk5 (ref. 2). Here we describe novel synthetic compounds that have a unique mode of binding to PPAR gamma, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPAR gamma drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPAR gamma.

引用

页码：477 / U131

页数：7

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