최장현 (Harvard Medical School)

한빛사논문

조회5,227

Harvard Medical School

CV File 273 kb

Nature, 477, 477–481 (22 September 2011) | Published online 04 September 2011 | doi:10.1038/nature10383 Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation

Abstract

Jang Hyun Choi^1*, Alexander S. Banks^1*, Theodore M. Kamenecka^2,4*, Scott A. Busby^3*, Michael J. Chalmers³, Naresh Kumar³, Dana S. Kuruvilla³, Youseung Shin², Yuanjun He², John B. Bruning⁵, David P. Marciano³, Michael D. Cameron^2,3,4, Dina Laznik¹, Michael J. Jurczak⁶, Stephan C. Schürer⁷, Dušica Vidović⁷, Gerald I. Shulman⁶, Bruce M. Spiegelman¹ & Patrick R. Griffin^2,3,4

¹Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, HarvardMedical School, Boston, Massachusetts 02115, USA. ²Translational Research Institute, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA. ³Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA. ⁴The Scripps Research Molecular Screening Center (SRMSC), The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA. ⁵Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128, USA. ⁶Howard Hughes Medical Institute, Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA. 7Center for Computational Science, University of Miami, Miami, Florida 33136, USA.
*These authors contributed equally to this work.

PPARγ is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone¹. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5 (ref. 2). Here we describe novel synthetic compounds that have a unique mode of binding to PPARγ, 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 PPARγ 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 PPARγ.

논문정보

형식Research article
게재일2011년 09월 (BRIC 등록일 )
연구진국외 연구진
분야 생명과학 > 세포생물학

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