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  • 1
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    Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-05-30
    Description: Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis; dysregulation of this axis causes diabetes. PGC-1alpha (peroxisome-proliferator-activated receptor-gamma coactivator-1alpha) links insulin signalling to the expression of glucose and lipid metabolic genes. The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1alpha. Although insulin is a mitogenic signal in proliferative cells, whether components of the cell cycle machinery contribute to its metabolic action is poorly understood. Here we report that in mice insulin activates cyclin D1-cyclin-dependent kinase 4 (Cdk4), which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen, we identify a Cdk4 inhibitor that potently decreases PGC-1alpha acetylation. Insulin/GSK-3beta (glycogen synthase kinase 3-beta) signalling induces cyclin D1 protein stability by sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 messenger RNA transcripts. Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1alpha activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycaemia. In diabetic models, cyclin D1-Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycaemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076706/" 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/PMC4076706/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Yoonjin -- Dominy, John E -- Choi, Yoon Jong -- Jurczak, Michael -- Tolliday, Nicola -- Camporez, Joao Paulo -- Chim, Helen -- Lim, Ji-Hong -- Ruan, Hai-Bin -- Yang, Xiaoyong -- Vazquez, Francisca -- Sicinski, Piotr -- Shulman, Gerald I -- Puigserver, Pere -- DK059635/DK/NIDDK NIH HHS/ -- F32 DK083871/DK/NIDDK NIH HHS/ -- P30 DK034989/DK/NIDDK NIH HHS/ -- R01 CA083688/CA/NCI NIH HHS/ -- R01 CA108420/CA/NCI NIH HHS/ -- R01 DK069966/DK/NIDDK NIH HHS/ -- R01 DK089098/DK/NIDDK NIH HHS/ -- R01069966/PHS HHS/ -- R03 DA032468/DA/NIDA NIH HHS/ -- R03 MH092174/MH/NIMH NIH HHS/ -- R24 DK080261/DK/NIDDK NIH HHS/ -- R24DK080261-06/DK/NIDDK NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 Jun 26;510(7506):547-51. doi: 10.1038/nature13267. Epub 2014 May 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Yale's Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA. ; Chemical Biology Platform, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02141, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24870244" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Amino Acids/pharmacology ; Animals ; *Cell Cycle ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Cells, Cultured ; Cyclin D1/deficiency/genetics/*metabolism ; Cyclin-Dependent Kinase 4/antagonists & inhibitors/*metabolism ; Diabetes Mellitus/metabolism ; Enzyme Activation ; Fasting ; Gene Deletion ; Gluconeogenesis/genetics ; Glucose/*metabolism ; Glycogen Synthase Kinase 3/metabolism ; Hepatocytes/cytology/drug effects/metabolism ; Histone Acetyltransferases/metabolism ; Homeostasis ; Humans ; Hyperglycemia/metabolism ; Hyperinsulinism/metabolism ; Insulin/*metabolism ; Male ; Mice ; Phosphorylation ; RNA, Messenger/analysis/genetics ; *Signal Transduction ; Transcription Factors/metabolism ; Transcription, Genetic/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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  • 2
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    Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-02-03
    Description: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal that inflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic tumour-necrosis factor (TNF)-alpha expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276682/" 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/PMC3276682/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Henao-Mejia, Jorge -- Elinav, Eran -- Jin, Chengcheng -- Hao, Liming -- Mehal, Wajahat Z -- Strowig, Till -- Thaiss, Christoph A -- Kau, Andrew L -- Eisenbarth, Stephanie C -- Jurczak, Michael J -- Camporez, Joao-Paulo -- Shulman, Gerald I -- Gordon, Jeffrey I -- Hoffman, Hal M -- Flavell, Richard A -- K08A1085038/PHS HHS/ -- P30 DK-45735/DK/NIDDK NIH HHS/ -- P30 DK045735/DK/NIDDK NIH HHS/ -- P30 DK045735-14/DK/NIDDK NIH HHS/ -- R01 DK-40936/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R01DK076674-01/DK/NIDDK NIH HHS/ -- R24 DK-085638/DK/NIDDK NIH HHS/ -- T32HL007974/HL/NHLBI NIH HHS/ -- U24 DK-059635/DK/NIDDK NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 1;482(7384):179-85. doi: 10.1038/nature10809.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22297845" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins ; Carrier Proteins/metabolism ; Choline ; Colon/microbiology ; Cytoskeletal Proteins/deficiency ; Disease Models, Animal ; *Disease Progression ; Fatty Liver/genetics/*metabolism/*pathology ; Inflammasomes/*metabolism ; Inflammation/metabolism/pathology ; Interleukin-18/deficiency ; Male ; Metagenome ; Methionine/deficiency ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease ; Obesity/*metabolism/*pathology ; RNA, Ribosomal, 16S/genetics ; Receptors, Cell Surface/metabolism ; Toll-Like Receptor 4/deficiency/metabolism ; Toll-Like Receptor 9/deficiency/metabolism ; Tumor Necrosis Factor-alpha/deficiency/metabolism
    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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    An ERK/Cdk5 axis controls the diabetogenic actions of PPARgamma (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-11-20
    Description: Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARgamma (peroxisome proliferator-activated receptor gamma) at serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPARgamma, such as the thiazolidinediones and PPARgamma partial agonists or non-agonists. For a better understanding of the importance of this obesity-linked PPARgamma phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPARgamma phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPARgamma in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wild-type and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPARgamma function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297557/" 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/PMC4297557/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Banks, Alexander S -- McAllister, Fiona E -- Camporez, Joao Paulo G -- Zushin, Peter-James H -- Jurczak, Michael J -- Laznik-Bogoslavski, Dina -- Shulman, Gerald I -- Gygi, Steven P -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- DK93638/DK/NIDDK NIH HHS/ -- K01 DK093638/DK/NIDDK NIH HHS/ -- R01 DK031405/DK/NIDDK NIH HHS/ -- England -- Nature. 2015 Jan 15;517(7534):391-5. doi: 10.1038/nature13887. Epub 2014 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Yale Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA. ; Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ; 1] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [2] 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/25409143" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/enzymology/metabolism ; Adipose Tissue/cytology/enzymology/metabolism ; Animals ; Cell Proliferation ; Cells, Cultured ; Cyclin-Dependent Kinase 5/deficiency/*metabolism ; Diabetes Mellitus/*metabolism ; Diet, High-Fat ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; Insulin Resistance ; MAP Kinase Kinase 2/antagonists & inhibitors/metabolism ; MAP Kinase Signaling System ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; PPAR gamma/chemistry/*metabolism ; Phosphorylation
    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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  • 4
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    Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-05-23
    Description: Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia. For over half a century, this agent has been prescribed to patients with type 2 diabetes worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. Here we show that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis. Acute and chronic low-dose metformin treatment effectively reduced endogenous glucose production, while increasing cytosolic redox and decreasing mitochondrial redox states. Antisense oligonucleotide knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats resulted in a phenotype akin to chronic metformin treatment, and abrogated metformin-mediated increases in cytosolic redox state, decreases in plasma glucose concentrations, and inhibition of endogenous glucose production. These findings were replicated in whole-body mitochondrial glycerophosphate dehydrogenase knockout mice. These results have significant implications for understanding the mechanism of metformin's blood glucose lowering effects and provide a new therapeutic target for type 2 diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074244/" 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/PMC4074244/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Madiraju, Anila K -- Erion, Derek M -- Rahimi, Yasmeen -- Zhang, Xian-Man -- Braddock, Demetrios T -- Albright, Ronald A -- Prigaro, Brett J -- Wood, John L -- Bhanot, Sanjay -- MacDonald, Michael J -- Jurczak, Michael J -- Camporez, Joao-Paulo -- Lee, Hui-Young -- Cline, Gary W -- Samuel, Varman T -- Kibbey, Richard G -- Shulman, Gerald I -- K01 DK-099402/DK/NIDDK NIH HHS/ -- P30 DK-034989/DK/NIDDK NIH HHS/ -- P30 DK-45735/DK/NIDDK NIH HHS/ -- P30 DK034989/DK/NIDDK NIH HHS/ -- P30 DK045735/DK/NIDDK NIH HHS/ -- R01 DK-092606/DK/NIDDK NIH HHS/ -- R01 DK-28348/DK/NIDDK NIH HHS/ -- R01 DK-40936/DK/NIDDK NIH HHS/ -- R01 DK028348/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R01 DK092606/DK/NIDDK NIH HHS/ -- R24 DK-085638/DK/NIDDK NIH HHS/ -- R24 DK085638/DK/NIDDK NIH HHS/ -- U24 DK-059635/DK/NIDDK NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- UL1 TR000142/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 26;510(7506):542-6. doi: 10.1038/nature13270. Epub 2014 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA. ; Cancer Prevention Research Institute of Texas Scholar, Department of Chemistry and Biochemistry, Baylor University, Waco, Texas 76798, USA. ; Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, California 92010, USA. ; University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA, 53706. ; 1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; 1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA [4] Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark, DK-2200.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24847880" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Glucose/analysis/biosynthesis ; Cells, Cultured ; Diabetes Mellitus, Type 2/drug therapy/enzymology/metabolism ; Gluconeogenesis/*drug effects ; Glycerolphosphate Dehydrogenase/*antagonists & ; inhibitors/deficiency/genetics/metabolism ; Humans ; Hypoglycemic Agents/pharmacology ; Insulin/secretion ; Lactic Acid/metabolism ; Liver/drug effects/metabolism ; Male ; Metformin/*pharmacology ; Mice, Knockout ; Mitochondria/*enzymology ; Oxidation-Reduction/drug effects ; Rats ; Rats, Sprague-Dawley
    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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