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  • 1
    Publication Date: 2001-06-02
    Description: Glucose homeostasis depends on insulin responsiveness in target tissues, most importantly, muscle and liver. The critical initial steps in insulin action include phosphorylation of scaffolding proteins and activation of phosphatidylinositol 3-kinase. These early events lead to activation of the serine-threonine protein kinase Akt, also known as protein kinase B. We show that mice deficient in Akt2 are impaired in the ability of insulin to lower blood glucose because of defects in the action of the hormone on liver and skeletal muscle. These data establish Akt2 as an essential gene in the maintenance of normal glucose homeostasis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cho, H -- Mu, J -- Kim, J K -- Thorvaldsen, J L -- Chu, Q -- Crenshaw, E B 3rd -- Kaestner, K H -- Bartolomei, M S -- Shulman, G I -- Birnbaum, M J -- GM07229/GM/NIGMS NIH HHS/ -- P30 19525/PHS HHS/ -- P30 DK50306/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R01 DK56886/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2001 Jun 1;292(5522):1728-31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11387480" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Glucose/metabolism ; Deoxyglucose/metabolism ; Diabetes Mellitus, Type 2/*metabolism ; Female ; Gene Targeting ; Glucose/*metabolism ; Glucose Clamp Technique ; Glucose Tolerance Test ; Homeostasis ; Insulin/administration & dosage/blood/*metabolism ; *Insulin Resistance/genetics/physiology ; Islets of Langerhans/cytology/physiology ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Muscle, Skeletal/enzymology/metabolism ; *Protein-Serine-Threonine Kinases ; Proto-Oncogene Proteins/*genetics/*metabolism ; Proto-Oncogene Proteins c-akt ; Signal Transduction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2008-08-01
    Description: The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein (NPY/AgRP neurons). However, the intracellular mechanisms triggered by ghrelin to alter NPY/AgRP neuronal activity are poorly understood. Here we show that ghrelin initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein 2 (UCP2). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons, for ghrelin-triggered synaptic plasticity of pro-opiomelanocortin-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK, CPT1 and free radicals that are scavenged by UCP2. These results reveal a signalling modality connecting mitochondria-mediated effects of G-protein-coupled receptors on neuronal function and associated behaviour.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101536/" 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/PMC4101536/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Andrews, Zane B -- Liu, Zhong-Wu -- Walllingford, Nicholas -- Erion, Derek M -- Borok, Erzsebet -- Friedman, Jeffery M -- Tschop, Matthias H -- Shanabrough, Marya -- Cline, Gary -- Shulman, Gerald I -- Coppola, Anna -- Gao, Xiao-Bing -- Horvath, Tamas L -- Diano, Sabrina -- R01 AG022880/AG/NIA NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Aug 14;454(7206):846-51. doi: 10.1038/nature07181. Epub 2008 Jul 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Comparative Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, Howard Hughes Medical Institute, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18668043" target="_blank"〉PubMed〈/a〉
    Keywords: Agouti-Related Protein/genetics/*metabolism ; Animals ; Carnitine O-Palmitoyltransferase/metabolism ; Fatty Acids/metabolism ; Feeding Behavior/drug effects ; Gene Expression Regulation/drug effects ; Ghrelin/*metabolism/pharmacology ; Hypothalamus/drug effects/metabolism ; Ion Channels/genetics/*metabolism ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mice ; Mitochondria/drug effects/physiology ; Mitochondrial Proteins/genetics/*metabolism ; Neurons/drug effects/*metabolism ; Neuropeptide Y/genetics/*metabolism ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Synapses/drug effects/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 1991-10-25
    Description: The rate of net hepatic glycogenolysis was assessed in humans by serially measuring hepatic glycogen concentration at 3- to 12-hour intervals during a 68-hour fast with 13C nuclear magnetic resonance spectroscopy. The net rate of gluconeogenesis was calculated by subtracting the rate of net hepatic glycogenolysis from the rate of glucose production in the whole body measured with tritiated glucose. Gluconeogenesis accounted for 64 +/- 5% (mean +/- standard error of the mean) of total glucose production during the first 22 hours of fasting. In the subsequent 14-hour and 18-hour periods of the fast, gluconeogenesis accounted for 82 +/- 5% and 96 +/- 1% of total glucose production, respectively. These data show that gluconeogenesis accounts for a substantial fraction of total glucose production even during the first 22 hours of a fast in humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rothman, D L -- Magnusson, I -- Katz, L D -- Shulman, R G -- Shulman, G I -- DK-34576/DK/NIDDK NIH HHS/ -- DK-40936/DK/NIDDK NIH HHS/ -- MO1-RR-00125-26/RR/NCRR NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 1991 Oct 25;254(5031):573-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1948033" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Blood Glucose/metabolism ; Carbon Isotopes ; Fasting ; Female ; Glucagon/blood ; *Gluconeogenesis ; Humans ; Hydrocortisone/blood ; Insulin/blood ; Kinetics ; Liver/*metabolism ; Liver Glycogen/*metabolism ; Magnetic Resonance Spectroscopy/methods ; Male ; Nitrogen/*urine
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2004-10-23
    Description: Hypertension and dyslipidemia are risk factors for atherosclerosis and occur together more often than expected by chance. Although this clustering suggests shared causation, unifying factors remain unknown. We describe a large kindred with a syndrome including hypertension, hypercholesterolemia, and hypomagnesemia. Each phenotype is transmitted on the maternal lineage with a pattern indicating mitochondrial inheritance. Analysis of the mitochondrial genome of the maternal lineage identified a homoplasmic mutation substituting cytidine for uridine immediately 5' to the mitochondrial transfer RNA(Ile) anticodon. Uridine at this position is nearly invariate among transfer RNAs because of its role in stabilizing the anticodon loop. Given the known loss of mitochondrial function with aging, these findings may have implications for the common clustering of these metabolic disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033655/" 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/PMC3033655/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wilson, Frederick H -- Hariri, Ali -- Farhi, Anita -- Zhao, Hongyu -- Petersen, Kitt Falk -- Toka, Hakan R -- Nelson-Williams, Carol -- Raja, Khalid M -- Kashgarian, Michael -- Shulman, Gerald I -- Scheinman, Steven J -- Lifton, Richard P -- MO1 RR-00125/RR/NCRR NIH HHS/ -- P50 HL-55007/HL/NHLBI NIH HHS/ -- R01 AG023686/AG/NIA NIH HHS/ -- R01 AG023686-01A1/AG/NIA NIH HHS/ -- R01 AG023686-02/AG/NIA NIH HHS/ -- R01 AG023686-03/AG/NIA NIH HHS/ -- R01 AG023686-04/AG/NIA NIH HHS/ -- R01 DK-49230/DK/NIDDK NIH HHS/ -- R01 DK049230/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2004 Nov 12;306(5699):1190-4. Epub 2004 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15498972" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aging ; Anticodon ; Body Mass Index ; Cluster Analysis ; Cytidine ; *Extrachromosomal Inheritance ; Female ; Humans ; Hypercholesterolemia/*genetics/physiopathology ; Hypertension/*genetics/physiopathology ; Magnesium/*blood/urine ; Male ; Metabolic Syndrome X/genetics ; Middle Aged ; Mitochondria/*genetics/metabolism ; Mitochondria, Muscle/metabolism/pathology ; Muscle Fibers, Skeletal/pathology ; *Mutation ; Pedigree ; Phenotype ; RNA/genetics ; RNA, Transfer, Ile/*genetics ; Syndrome ; Thymidine ; Uridine
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2005-01-22
    Description: Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic beta cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lowell, Bradford B -- Shulman, Gerald I -- R01 DK040936/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2005 Jan 21;307(5708):384-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Harvard Medical School, Boston, MA 02215, USA. blowell@bidmc.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15662004" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate ; Animals ; Diabetes Mellitus, Type 2/*physiopathology ; Fatty Acids/metabolism ; Gene Expression Regulation ; Glucose/metabolism ; Humans ; Hyperglycemia/physiopathology ; Insulin/secretion ; Insulin Resistance ; Ion Channels ; Islets of Langerhans/cytology/*physiology/secretion ; Liver/metabolism ; Membrane Transport Proteins/genetics/metabolism ; Mitochondria/*physiology ; Mitochondrial Proteins/genetics/metabolism ; Models, Biological ; Muscle, Skeletal/metabolism ; Obesity/physiopathology ; Oxidation-Reduction ; Oxidative Phosphorylation ; Superoxides/metabolism ; Transcription Factors/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2003-05-17
    Description: Insulin resistance is a major factor in the pathogenesis of type 2 diabetes in the elderly. To investigate how insulin resistance arises, we studied healthy, lean, elderly and young participants matched for lean body mass and fat mass. Elderly study participants were markedly insulin-resistant as compared with young controls, and this resistance was attributable to reduced insulin-stimulated muscle glucose metabolism. These changes were associated with increased fat accumulation in muscle and liver tissue assessed by 1H nuclear magnetic resonance (NMR) spectroscopy, and with a approximately 40% reduction in mitochondrial oxidative and phosphorylation activity, as assessed by in vivo 13C/31P NMR spectroscopy. These data support the hypothesis that an age-associated decline in mitochondrial function contributes to insulin resistance in the elderly.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004429/" 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/PMC3004429/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Petersen, Kitt Falk -- Befroy, Douglas -- Dufour, Sylvie -- Dziura, James -- Ariyan, Charlotte -- Rothman, Douglas L -- DiPietro, Loretta -- Cline, Gary W -- Shulman, Gerald I -- K-23 DK-02347/DK/NIDDK NIH HHS/ -- K23 DK002734/DK/NIDDK NIH HHS/ -- K23 DK002734-04/DK/NIDDK NIH HHS/ -- M01 RR-00125/RR/NCRR NIH HHS/ -- P30 DK-45735/DK/NIDDK NIH HHS/ -- P60 AG-10469/AG/NIA NIH HHS/ -- R01 AG-09872/AG/NIA NIH HHS/ -- R01 AG023686/AG/NIA NIH HHS/ -- R01 AG023686-01A1/AG/NIA NIH HHS/ -- R01 DK-49230/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2003 May 16;300(5622):1140-2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12750520" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/metabolism ; Blood Glucose/metabolism ; Body Mass Index ; Female ; Humans ; Insulin/metabolism ; *Insulin Resistance ; Liver/metabolism ; Male ; Middle Aged ; Mitochondria/*metabolism ; Mitochondrial Diseases/blood/*complications/metabolism ; Muscle, Skeletal/metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Oxidation-Reduction ; Oxygen Consumption ; Phosphorylation ; Triglycerides/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    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
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  • 8
    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
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  • 9
    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
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  • 10
    Publication Date: 2014-06-06
    Description: Non-alcoholic fatty liver disease and its downstream sequelae, hepatic insulin resistance and type 2 diabetes, are rapidly growing epidemics, which lead to increased morbidity and mortality rates, and soaring health-care costs. Developing interventions requires a comprehensive understanding of the mechanisms by which excess hepatic lipid develops and causes hepatic insulin resistance and type 2 diabetes. Proposed mechanisms implicate various lipid species, inflammatory signalling and other cellular modifications. Studies in mice and humans have elucidated a key role for hepatic diacylglycerol activation of protein kinase Cepsilon in triggering hepatic insulin resistance. Therapeutic approaches based on this mechanism could alleviate the related epidemics of non-alcoholic fatty liver disease and type 2 diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489847/" 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/PMC4489847/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perry, Rachel J -- Samuel, Varman T -- Petersen, Kitt F -- Shulman, Gerald I -- I01 BX000901/BX/BLRD VA/ -- P30 DK-45735/DK/NIDDK NIH HHS/ -- P30 DK034989/DK/NIDDK NIH HHS/ -- R01 AG-23686/AG/NIA NIH HHS/ -- R01 DK-40936/DK/NIDDK NIH HHS/ -- R01 DK-49230/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R24 DK-085836/DK/NIDDK NIH HHS/ -- T32-DK101019/DK/NIDDK NIH HHS/ -- U24 DK-059635/DK/NIDDK NIH HHS/ -- UL1 RR-024139/RR/NCRR NIH HHS/ -- England -- Nature. 2014 Jun 5;510(7503):84-91. doi: 10.1038/nature13478.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, 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] VA Connecticut Healthcare System West Haven, Connecticut 06516, USA. ; 1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA. [2] Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen DK-2200, Denmark. ; 1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA. [2] Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen DK-2200, Denmark. [3] Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. [4] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06535-8012, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24899308" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Diabetes Mellitus, Type 2/drug therapy/*metabolism ; Diglycerides/metabolism ; Fatty Liver/drug therapy/metabolism ; Humans ; Hyperglycemia/metabolism ; *Insulin Resistance ; *Lipid Metabolism ; *Lipids/biosynthesis ; Lipodystrophy/metabolism ; Lipogenesis ; Liver/*metabolism ; Muscle, Skeletal/metabolism ; Non-alcoholic Fatty Liver Disease ; Triglycerides/biosynthesis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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