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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
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    Electronic ISSN: 1476-4687
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  • 2
    Publication Date: 2016-03-31
    Description: Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1). Thermogenesis from these adipocytes can combat obesity and diabetes, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chouchani, Edward T -- Kazak, Lawrence -- Jedrychowski, Mark P -- Lu, Gina Z -- Erickson, Brian K -- Szpyt, John -- Pierce, Kerry A -- Laznik-Bogoslavski, Dina -- Vetrivelan, Ramalingam -- Clish, Clary B -- Robinson, Alan J -- Gygi, Steve P -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2016 Apr 7;532(7597):112-6. doi: 10.1038/nature17399. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; Department of Neurology, Harvard Medical School, Boston, Massachusetts 02215, USA. ; MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027295" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/chemistry/cytology/metabolism ; Animals ; Cell Respiration ; Cysteine/*chemistry/genetics/metabolism ; *Energy Metabolism/drug effects ; Female ; Humans ; Ion Channels/*chemistry/deficiency/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/*metabolism ; Mitochondrial Proteins/*chemistry/deficiency/genetics/*metabolism ; Mutant Proteins/chemistry/genetics/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; Sulfhydryl Compounds/metabolism ; *Thermogenesis/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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  • 3
    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
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2008-08-23
    Description: Brown fat can increase energy expenditure and protect against obesity through a specialized program of uncoupled respiration. Here we show by in vivo fate mapping that brown, but not white, fat cells arise from precursors that express Myf5, a gene previously thought to be expressed only in the myogenic lineage. We also demonstrate that the transcriptional regulator PRDM16 (PRD1-BF1-RIZ1 homologous domain containing 16) controls a bidirectional cell fate switch between skeletal myoblasts and brown fat cells. Loss of PRDM16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of PRDM16 in myoblasts induces their differentiation into brown fat cells. PRDM16 stimulates brown adipogenesis by binding to PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) and activating its transcriptional function. Finally, Prdm16-deficient brown fat displays an abnormal morphology, reduced thermogenic gene expression and elevated expression of muscle-specific genes. Taken together, these data indicate that PRDM16 specifies the brown fat lineage from a progenitor that expresses myoblast markers and is not involved in white adipogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583329/" 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/PMC2583329/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seale, Patrick -- Bjork, Bryan -- Yang, Wenli -- Kajimura, Shingo -- Chin, Sherry -- Kuang, Shihuan -- Scime, Anthony -- Devarakonda, Srikripa -- Conroe, Heather M -- Erdjument-Bromage, Hediye -- Tempst, Paul -- Rudnicki, Michael A -- Beier, David R -- Spiegelman, Bruce M -- R01 AR044031/AR/NIAMS NIH HHS/ -- R01 AR044031-11/AR/NIAMS NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- R37 DK031405-27/DK/NIDDK NIH HHS/ -- England -- Nature. 2008 Aug 21;454(7207):961-7. doi: 10.1038/nature07182.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, 1 Jimmy Fund Way, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18719582" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes, Brown/cytology/*metabolism ; Adipocytes, White/metabolism ; Adipose Tissue, Brown/cytology ; Animals ; COS Cells ; *Cell Differentiation/genetics ; Cell Line ; Cercopithecus aethiops ; DNA-Binding Proteins/genetics/*metabolism ; *Gene Expression Regulation, Developmental ; Male ; Mice ; Muscle Development/genetics ; Muscle, Skeletal/cytology/growth & development/*metabolism ; Myogenic Regulatory Factor 5/genetics ; PPAR gamma/genetics ; Transcription Factors/genetics/*metabolism
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  • 5
    Publication Date: 2010-03-05
    Description: The worldwide epidemic of obesity has increased the urgency to develop a deeper understanding of physiological systems related to energy balance and energy storage, including the mechanisms controlling the development of fat cells (adipocytes). The differentiation of committed preadipocytes to adipocytes is controlled by PPARgamma and several other transcription factors, but the molecular basis for preadipocyte determination is not understood. Using a new method for the quantitative analysis of transcriptional components, we identified the zinc-finger protein Zfp423 as a factor enriched in preadipose versus non-preadipose fibroblasts. Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and diminishes the ability of these cells to differentiate. Furthermore, both brown and white adipocyte differentiation is markedly impaired in Zfp423-deficient mouse embryos. Zfp423 regulates Pparg expression, in part, through amplification of the BMP signalling pathway, an effect dependent on the SMAD-binding capacity of Zfp423. This study identifies Zfp423 as a transcriptional regulator of preadipocyte determination.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845731/" 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/PMC2845731/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gupta, Rana K -- Arany, Zoltan -- Seale, Patrick -- Mepani, Rina J -- Ye, Li -- Conroe, Heather M -- Roby, Yang A -- Kulaga, Heather -- Reed, Randall R -- Spiegelman, Bruce M -- DK081605/DK/NIDDK NIH HHS/ -- DK31405/DK/NIDDK NIH HHS/ -- F32 DK079507/DK/NIDDK NIH HHS/ -- F32 DK079507-01/DK/NIDDK NIH HHS/ -- F32 DK079507-02/DK/NIDDK NIH HHS/ -- K08 HL79172-01/HL/NHLBI NIH HHS/ -- K99 DK081605/DK/NIDDK NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-14/DK/NIDDK NIH HHS/ -- R01 DC008295/DC/NIDCD NIH HHS/ -- R01 DC008295-04/DC/NIDCD NIH HHS/ -- R01DC008295/DC/NIDCD NIH HHS/ -- England -- Nature. 2010 Mar 25;464(7288):619-23. doi: 10.1038/nature08816. Epub 2010 Mar 3.〈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/20200519" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue/*cytology ; Animals ; *Cell Differentiation ; DNA-Binding Proteins/*metabolism ; Female ; *Gene Expression Regulation, Developmental ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NIH 3T3 Cells ; PPAR gamma/metabolism ; Protein Structure, Tertiary ; Smad Proteins/metabolism ; Transcription Factors/*metabolism
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  • 6
    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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  • 7
    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
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    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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  • 9
    Publication Date: 2014-07-22
    Description: Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat. How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224962/" 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/PMC4224962/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kir, Serkan -- White, James P -- Kleiner, Sandra -- Kazak, Lawrence -- Cohen, Paul -- Baracos, Vickie E -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 Sep 4;513(7516):100-4. doi: 10.1038/nature13528. Epub 2014 Jul 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Department of Oncology, Division of Palliative Care Medicine, University of Alberta, Edmonton T6G 1Z2, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043053" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/cytology/drug effects/*metabolism/pathology ; Animals ; Cachexia/*metabolism/pathology ; Carcinoma, Lewis Lung/genetics/*metabolism/*pathology ; Culture Media, Conditioned/pharmacology ; Energy Metabolism/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Male ; Mice ; Muscle, Skeletal/metabolism/pathology ; Organ Size/drug effects ; Parathyroid Hormone-Related Protein/antagonists & inhibitors/*metabolism ; Thermogenesis/drug effects/genetics
    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: 2008-07-25
    Description: Inadequate physical activity is linked to many chronic diseases. But the mechanisms that tie muscle activity to health are unclear. The transcriptional coactivator PGC1alpha has recently been shown to regulate several exercise-associated aspects of muscle function. We propose that this protein controls muscle plasticity, suppresses a broad inflammatory response and mediates the beneficial effects of exercise.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587487/" 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/PMC2587487/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Handschin, Christoph -- Spiegelman, Bruce M -- R01 DK054477/DK/NIDDK NIH HHS/ -- R01 DK054477-09A1/DK/NIDDK NIH HHS/ -- England -- Nature. 2008 Jul 24;454(7203):463-9. doi: 10.1038/nature07206.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, CH-8057 Zurich, Switzerland. christoph.handschin@access.uzh.ch〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18650917" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chronic Disease ; Exercise/*physiology ; Humans ; Inflammation/genetics/*metabolism ; Muscle, Skeletal/metabolism/physiology ; Obesity/genetics/immunology/physiopathology ; 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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