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  • 1
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    Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5 (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-07-24
    Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987584/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987584/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choi, Jang Hyun -- Banks, Alexander S -- Estall, Jennifer L -- Kajimura, Shingo -- Bostrom, Pontus -- Laznik, Dina -- Ruas, Jorge L -- Chalmers, Michael J -- Kamenecka, Theodore M -- Bluher, Matthias -- Griffin, Patrick R -- Spiegelman, Bruce M -- DK087853/DK/NIDDK NIH HHS/ -- DK31405/DK/NIDDK NIH HHS/ -- K99 DK087853/DK/NIDDK NIH HHS/ -- R01 GM084041/GM/NIGMS NIH HHS/ -- R01 GM084041-03/GM/NIGMS NIH HHS/ -- R01-GM084041/GM/NIGMS NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- R37 DK031405-30/DK/NIDDK NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- U54 MH084512/MH/NIMH NIH HHS/ -- U54 MH084512-020010/MH/NIMH NIH HHS/ -- U54-MH084512/MH/NIMH NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2010 Jul 22;466(7305):451-6. doi: 10.1038/nature09291.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20651683" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue/drug effects/metabolism/physiopathology ; Amino Acid Sequence ; Animals ; Cell Line ; Cyclin-Dependent Kinase 5/*antagonists & inhibitors/genetics/metabolism ; Diabetes Mellitus, Experimental/complications/*drug therapy/metabolism ; Dietary Fats/pharmacology ; Humans ; Insulin/metabolism ; Ligands ; Mice ; Models, Molecular ; Obesity/chemically induced/complications/*metabolism/physiopathology ; PPAR gamma/agonists/*metabolism ; Phosphorylation/drug effects ; Phosphoserine/metabolism ; Protein Conformation ; Thiazolidinediones/*pharmacology/therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Antidiabetic actions of a non-agonist PPARgamma ligand blocking Cdk5-mediated phosphorylation (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-09-06
    Description: PPARgamma is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARgamma-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARgamma by Cdk5. Here we describe novel synthetic compounds that have a unique mode of binding to PPARgamma, 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 PPARgamma 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 PPARgamma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179551/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179551/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choi, Jang Hyun -- Banks, Alexander S -- Kamenecka, Theodore M -- Busby, Scott A -- Chalmers, Michael J -- Kumar, Naresh -- Kuruvilla, Dana S -- Shin, Youseung -- He, Yuanjun -- Bruning, John B -- Marciano, David P -- Cameron, Michael D -- Laznik, Dina -- Jurczak, Michael J -- Schurer, Stephan C -- Vidovic, Dusica -- Shulman, Gerald I -- Spiegelman, Bruce M -- Griffin, Patrick R -- 1RC4DK090861/DK/NIDDK NIH HHS/ -- DK31405/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R01 GM084041/GM/NIGMS NIH HHS/ -- R01 GM084041-03/GM/NIGMS NIH HHS/ -- R01-GM084041/GM/NIGMS NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- R37 DK031405-30/DK/NIDDK NIH HHS/ -- R37 DK031405-31/DK/NIDDK NIH HHS/ -- RC4 DK090861/DK/NIDDK NIH HHS/ -- RC4 DK090861-01/DK/NIDDK NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- U54 MH074404/MH/NIMH NIH HHS/ -- U54 MH074404-01/MH/NIMH NIH HHS/ -- U54-MH074404/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Sep 4;477(7365):477-81. doi: 10.1038/nature10383.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21892191" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3-L1 Cells ; Adipocytes/drug effects/metabolism ; Adipose Tissue, White/drug effects/metabolism ; Animals ; Biphenyl Compounds/chemistry/pharmacology ; Body Fluids/drug effects ; COS Cells ; Cercopithecus aethiops ; Cyclin-Dependent Kinase 5/*antagonists & inhibitors ; Dietary Fats/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Hypoglycemic Agents/adverse effects/chemistry/*pharmacology ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Models, Molecular ; Obesity/chemically induced/metabolism ; Osteogenesis/drug effects ; PPAR gamma/agonists/chemistry/*metabolism ; Phosphorylation/drug effects ; Phosphoserine/metabolism ; Thiazolidinediones/adverse effects/pharmacology ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/pharmacology ; Weight Gain/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-04-19
    Description: T-helper cells that produce interleukin-17 (T(H)17 cells) are a recently identified CD4(+) T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors alpha and gammat (RORalpha and RORgammat, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both RORalpha and RORgammat and which inhibits T(H)17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORalpha and RORgammat, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine T(H)17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human T(H)17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORalpha and RORgammat to inhibit specifically T(H)17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148894/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148894/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Solt, Laura A -- Kumar, Naresh -- Nuhant, Philippe -- Wang, Yongjun -- Lauer, Janelle L -- Liu, Jin -- Istrate, Monica A -- Kamenecka, Theodore M -- Roush, William R -- Vidovic, Dusica -- Schurer, Stephan C -- Xu, Jihong -- Wagoner, Gail -- Drew, Paul D -- Griffin, Patrick R -- Burris, Thomas P -- DK080201/DK/NIDDK NIH HHS/ -- DK088499/DK/NIDDK NIH HHS/ -- DK089984/DK/NIDDK NIH HHS/ -- GM084041/GM/NIGMS NIH HHS/ -- MH084512/MH/NIMH NIH HHS/ -- R01 DK080201/DK/NIDDK NIH HHS/ -- R01 DK080201-06/DK/NIDDK NIH HHS/ -- R01 GM084041/GM/NIGMS NIH HHS/ -- R01 MH092769/MH/NIMH NIH HHS/ -- U54 MH084512/MH/NIMH NIH HHS/ -- U54 MH084512-02/MH/NIMH NIH HHS/ -- U54MH074404/MH/NIMH NIH HHS/ -- England -- Nature. 2011 Apr 28;472(7344):491-4. doi: 10.1038/nature10075. Epub 2011 Apr 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21499262" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmunity/*drug effects/immunology ; Cell Differentiation/*drug effects ; Drug Inverse Agonism ; HEK293 Cells ; Humans ; Interleukin-17/biosynthesis/immunology ; Interleukins/biosynthesis/immunology ; Ligands ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Nuclear Receptor Subfamily 1, Group F, Member 1/antagonists & ; inhibitors/genetics/metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & ; inhibitors/genetics/metabolism ; Sulfonamides/*pharmacology ; Th17 Cells/*cytology/drug effects/*immunology/secretion ; Thiazoles/*pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-31
    Description: Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-alpha and REV-ERB-beta have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343186/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343186/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Solt, Laura A -- Wang, Yongjun -- Banerjee, Subhashis -- Hughes, Travis -- Kojetin, Douglas J -- Lundasen, Thomas -- Shin, Youseung -- Liu, Jin -- Cameron, Michael D -- Noel, Romain -- Yoo, Seung-Hee -- Takahashi, Joseph S -- Butler, Andrew A -- Kamenecka, Theodore M -- Burris, Thomas P -- DK080201/DK/NIDDK NIH HHS/ -- DK088499/DK/NIDDK NIH HHS/ -- DK089984/DK/NIDDK NIH HHS/ -- MH092769/MH/NIMH NIH HHS/ -- R01 DK073189/DK/NIDDK NIH HHS/ -- R01 DK080201/DK/NIDDK NIH HHS/ -- R01 DK080201-05/DK/NIDDK NIH HHS/ -- R01 MH092769/MH/NIMH NIH HHS/ -- R01 MH092769-02/MH/NIMH NIH HHS/ -- R01 MH093429/MH/NIMH NIH HHS/ -- R01 MH093429-01A1/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 29;485(7396):62-8. doi: 10.1038/nature11030.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22460951" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue/drug effects/metabolism ; Animals ; Biological Clocks/drug effects/genetics/physiology ; Circadian Rhythm/*drug effects/genetics/*physiology ; Disease Models, Animal ; Energy Metabolism/*drug effects ; HEK293 Cells ; Humans ; Hypothalamus/drug effects/metabolism ; Liver/drug effects/metabolism ; Metabolome/drug effects ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Muscle, Skeletal/drug effects/metabolism ; Nuclear Receptor Subfamily 1, Group D, Member 1/*antagonists & ; inhibitors/metabolism ; Obesity/chemically induced/drug therapy/metabolism ; Pyrrolidines/*pharmacology ; Receptors, Cytoplasmic and Nuclear/*antagonists & inhibitors/metabolism ; Repressor Proteins/*antagonists & inhibitors/metabolism ; Thiophenes/*pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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