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  • 1
    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
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  • 2
    Publication Date: 2008-02-22
    Description: Ischaemia of the heart, brain and limbs is a leading cause of morbidity and mortality worldwide. Hypoxia stimulates the secretion of vascular endothelial growth factor (VEGF) and other angiogenic factors, leading to neovascularization and protection against ischaemic injury. Here we show that the transcriptional coactivator PGC-1alpha (peroxisome-proliferator-activated receptor-gamma coactivator-1alpha), a potent metabolic sensor and regulator, is induced by a lack of nutrients and oxygen, and PGC-1alpha powerfully regulates VEGF expression and angiogenesis in cultured muscle cells and skeletal muscle in vivo. PGC-1alpha-/- mice show a striking failure to reconstitute blood flow in a normal manner to the limb after an ischaemic insult, whereas transgenic expression of PGC-1alpha in skeletal muscle is protective. Surprisingly, the induction of VEGF by PGC-1alpha does not involve the canonical hypoxia response pathway and hypoxia inducible factor (HIF). Instead, PGC-1alpha coactivates the orphan nuclear receptor ERR-alpha (oestrogen-related receptor-alpha) on conserved binding sites found in the promoter and in a cluster within the first intron of the VEGF gene. Thus, PGC-1alpha and ERR-alpha, major regulators of mitochondrial function in response to exercise and other stimuli, also control a novel angiogenic pathway that delivers needed oxygen and substrates. PGC-1alpha may provide a novel therapeutic target for treating ischaemic diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arany, Zoltan -- Foo, Shi-Yin -- Ma, Yanhong -- Ruas, Jorge L -- Bommi-Reddy, Archana -- Girnun, Geoffrey -- Cooper, Marcus -- Laznik, Dina -- Chinsomboon, Jessica -- Rangwala, Shamina M -- Baek, Kwan Hyuck -- Rosenzweig, Anthony -- Spiegelman, Bruce M -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-12/DK/NIDDK NIH HHS/ -- R01 DK054477/DK/NIDDK NIH HHS/ -- England -- Nature. 2008 Feb 21;451(7181):1008-12. doi: 10.1038/nature06613.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. zarany1@partners.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18288196" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Hypoxia ; Cells, Cultured ; Gene Expression Regulation ; Hypoxia-Inducible Factor 1/metabolism ; Ischemia/*metabolism ; Mice ; Mice, Transgenic ; Muscle, Skeletal/metabolism ; *Neovascularization, Physiologic ; Oxygen/metabolism ; Receptors, Estrogen/metabolism ; Trans-Activators/deficiency/genetics/*metabolism ; Transcription Factors ; Transgenes/genetics ; Vascular Endothelial Growth Factor A/*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: 2012-01-13
    Description: Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-gamma co-activator-1 alpha (PGC1-alpha). Here we show in mouse that PGC1-alpha expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3522098/" 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/PMC3522098/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bostrom, Pontus -- Wu, Jun -- Jedrychowski, Mark P -- Korde, Anisha -- Ye, Li -- Lo, James C -- Rasbach, Kyle A -- Bostrom, Elisabeth Almer -- Choi, Jang Hyun -- Long, Jonathan Z -- Kajimura, Shingo -- Zingaretti, Maria Cristina -- Vind, Birgitte F -- Tu, Hua -- Cinti, Saverio -- Hojlund, Kurt -- Gygi, Steven P -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- DK54477/DK/NIDDK NIH HHS/ -- K99 DK087853/DK/NIDDK NIH HHS/ -- R01 DK054477/DK/NIDDK NIH HHS/ -- R01 DK061562/DK/NIDDK NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- England -- Nature. 2012 Jan 11;481(7382):463-8. doi: 10.1038/nature10777.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22237023" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/cytology/drug effects/metabolism ; Adipose Tissue, Brown/*cytology/drug effects/metabolism ; Adipose Tissue, White/*cytology/drug effects/metabolism ; Animals ; Cell Respiration/drug effects ; Cells, Cultured ; Culture Media, Conditioned/pharmacology ; Energy Metabolism/drug effects/genetics/physiology ; Exercise/physiology ; Gene Expression Regulation/drug effects/genetics ; Hormones/metabolism/secretion ; Humans ; Insulin Resistance/physiology ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Ion Channels/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Mitochondrial Proteins/metabolism ; Models, Animal ; Muscle Cells/metabolism ; Obesity/blood/chemically induced/prevention & control ; Physical Conditioning, Animal/physiology ; Plasma/chemistry ; Subcutaneous Fat/cytology/drug effects/metabolism ; *Thermogenesis/drug effects/genetics ; Trans-Activators/deficiency/genetics/*metabolism/secretion ; Transcription Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 1987-07-24
    Description: Adipsin is a serine protease homolog whose primary structure was predicted from the nucleotide sequence of a differentiation-dependent adipocyte messenger RNA. Immunoblots probed with antisera to synthetic peptides identify two forms of adipsin that are synthesized and secreted by 3T3 adipocytes. These proteins of 44 and 37 kilodaltons are converted to 25.5 kilodaltons by enzymatic deglycosylation. Although adipsin is principally synthesized in adipose tissue, it is also produced by sciatic nerve and is found in the bloodstream. Because of the apparent restriction of adipsin synthesis to tissues highly active in lipid metabolism, its presence in serum, and its modulation in altered metabolic states, this molecule may play a previously unrecognized role in systemic lipid metabolism or energy balance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cook, K S -- Min, H Y -- Johnson, D -- Chaplinsky, R J -- Flier, J S -- Hunt, C R -- Spiegelman, B M -- AM07230/AM/NIADDK NIH HHS/ -- AM31405/AM/NIADDK NIH HHS/ -- DK34605/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 1987 Jul 24;237(4813):402-5.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/3299705" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue/*enzymology ; Animals ; Cells, Cultured ; Complement Factor D ; Endopeptidases/blood/genetics/*secretion ; Male ; Mice ; Molecular Weight ; Organ Culture Techniques ; RNA, Messenger/genetics ; Sciatic Nerve/*enzymology ; *Serine Endopeptidases ; Transcription, Genetic
    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
    Publication Date: 1996-02-02
    Description: Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor (IR). Treatment of cultured murine adipocytes with TNF-alpha was shown to induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and convert IRS-1 into an inhibitor of the IR tyrosine kinase activity in vitro. Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF-alpha-mediated inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-alpha. An inhibitory form of IRS-1 was observed in muscle and fat tissues from obese rats. These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hotamisligil, G S -- Peraldi, P -- Budavari, A -- Ellis, R -- White, M F -- Spiegelman, B M -- DK 42539/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 1996 Feb 2;271(5249):665-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Biology, Dana-Farber Cancer Institute, Boston, MA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8571133" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/*metabolism ; Adipose Tissue/metabolism ; Animals ; Cells, Cultured ; Insulin/pharmacology ; Insulin Receptor Substrate Proteins ; Insulin Resistance/*physiology ; Male ; Mice ; Muscle, Skeletal/metabolism ; Obesity/*metabolism ; Phosphoproteins/metabolism/*physiology ; Phosphorylation ; Rats ; Rats, Zucker ; Receptor, Insulin/*antagonists & inhibitors/metabolism ; Serine/metabolism ; Signal Transduction ; Tumor Necrosis Factor-alpha/*pharmacology
    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: 2009-07-31
    Description: Brown adipose cells are specialized to dissipate chemical energy in the form of heat, as a physiological defence against cold and obesity. PRDM16 (PR domain containing 16) is a 140 kDa zinc finger protein that robustly induces brown fat determination and differentiation. Recent data suggests that brown fat cells arise in vivo from a Myf5-positive, myoblastic lineage by the action of PRDM16 (ref. 3); however, the molecular mechanisms responsible for this developmental switch is unclear. Here we show that PRDM16 forms a transcriptional complex with the active form of C/EBP-beta (also known as LAP), acting as a critical molecular unit that controls the cell fate switch from myoblastic precursors to brown fat cells. Forced expression of PRDM16 and C/EBP-beta is sufficient to induce a fully functional brown fat program in naive fibroblastic cells, including skin fibroblasts from mouse and man. Transplantation of fibroblasts expressing these two factors into mice gives rise to an ectopic fat pad with the morphological and biochemical characteristics of brown fat. Like endogenous brown fat, this synthetic brown fat tissue acts as a sink for glucose uptake, as determined by positron emission tomography with fluorodeoxyglucose. These data indicate that the PRDM16-C/EBP-beta complex initiates brown fat formation from myoblastic precursors, and may provide opportunities for the development of new therapeutics for obesity and type-2 diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754867/" 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/PMC2754867/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kajimura, Shingo -- Seale, Patrick -- Kubota, Kazuishi -- Lunsford, Elaine -- Frangioni, John V -- Gygi, Steven P -- Spiegelman, Bruce M -- DK081605/DK/NIDDK NIH HHS/ -- DK31405/DK/NIDDK NIH HHS/ -- GM67945/GM/NIGMS NIH HHS/ -- HG3456/HG/NHGRI NIH HHS/ -- K99 DK087853/DK/NIDDK NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- R37 DK031405-28/DK/NIDDK NIH HHS/ -- S10-RR-023010/RR/NCRR NIH HHS/ -- England -- Nature. 2009 Aug 27;460(7259):1154-8. doi: 10.1038/nature08262. Epub 2009 Jul 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19641492" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/*cytology/*metabolism ; Animals ; CCAAT-Enhancer-Binding Protein-beta/genetics/*metabolism ; Cell Differentiation ; Cell Line ; Cells, Cultured ; Choristoma/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Fibroblasts/cytology/metabolism ; Glucose/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes ; Myoblasts/*cytology/*metabolism ; Skin/cytology ; Transcription Factors/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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