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  • 1
    Publication Date: 2013-10-25
    Description: Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or use. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding and is repressed by Rev-erbalpha/beta and an HDAC3-containing complex during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARdelta-dependent de novo lipogenic pathway in the liver that modulates fat use by muscle via a circulating lipid. The nuclear receptor PPARdelta controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARdelta activation increases, whereas hepatocyte-Ppard deletion reduces, muscle fatty acid uptake. Unbiased metabolite profiling identifies phosphatidylcholine 18:0/18:1 (PC(18:0/18:1) as a serum lipid regulated by diurnal hepatic PPARdelta activity. PC(18:0/18:1) reduces postprandial lipid levels and increases fatty acid use through muscle PPARalpha. High-fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice (also known as Lepr(-/-)) improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy use in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARdelta-PC(18:0/18:1) signalling in metabolic disorders, including obesity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141623/" 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/PMC4141623/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Sihao -- Brown, Jonathan D -- Stanya, Kristopher J -- Homan, Edwin -- Leidl, Mathias -- Inouye, Karen -- Bhargava, Prerna -- Gangl, Matthew R -- Dai, Lingling -- Hatano, Ben -- Hotamisligil, Gokhan S -- Saghatelian, Alan -- Plutzky, Jorge -- Lee, Chih-Hao -- K08 HL105678/HL/NHLBI NIH HHS/ -- K08HL105678/HL/NHLBI NIH HHS/ -- P01 HL048743/HL/NHLBI NIH HHS/ -- R01 DK075046/DK/NIDDK NIH HHS/ -- R01DK075046/DK/NIDDK NIH HHS/ -- R01HL048743/HL/NHLBI NIH HHS/ -- T32 ES016645/ES/NIEHS NIH HHS/ -- England -- Nature. 2013 Oct 24;502(7472):550-4. doi: 10.1038/nature12710.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24153306" target="_blank"〉PubMed〈/a〉
    Keywords: Acetyl-CoA Carboxylase/metabolism ; Animals ; *Circadian Rhythm ; Diabetes Mellitus/metabolism ; Fatty Acids/*metabolism ; Gene Expression Regulation ; Homeostasis ; Lipids/*blood ; *Lipogenesis/genetics ; Liver/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Muscles/metabolism ; Obesity/metabolism ; PPAR delta/metabolism ; Phosphatidylcholines/blood ; Principal Component Analysis
    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: 2014-05-23
    Description: Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene, the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide(-/-) mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE's physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142213/" 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/PMC4142213/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maianti, Juan Pablo -- McFedries, Amanda -- Foda, Zachariah H -- Kleiner, Ralph E -- Du, Xiu Quan -- Leissring, Malcolm A -- Tang, Wei-Jen -- Charron, Maureen J -- Seeliger, Markus A -- Saghatelian, Alan -- Liu, David R -- DP2 OD002374/OD/NIH HHS/ -- F30 CA174152/CA/NCI NIH HHS/ -- P30 DK057521/DK/NIDDK NIH HHS/ -- P41 GM111244/GM/NIGMS NIH HHS/ -- R00 GM080097/GM/NIGMS NIH HHS/ -- R01 GM065865/GM/NIGMS NIH HHS/ -- R01 GM081539/GM/NIGMS NIH HHS/ -- R01 GM81539/GM/NIGMS NIH HHS/ -- T32 GM007598/GM/NIGMS NIH HHS/ -- T32 GM008444/GM/NIGMS NIH HHS/ -- UL1 TR000430/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jul 3;511(7507):94-8. doi: 10.1038/nature13297. Epub 2014 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA. ; Department of Pharmacological Sciences, Stony Brook University, 1 Circle Road, Stony Brook, New York 11794, USA. ; Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA. ; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, 3204 Biological Sciences III, Irvine, California 92697, USA. ; Ben-May Department for Cancer Research, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA. ; 1] Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA [2] Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24847884" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Blood Glucose/metabolism ; Catalytic Domain ; Diabetes Mellitus, Type 2/drug therapy/genetics ; Disease Models, Animal ; Gastric Emptying/drug effects ; Genetic Predisposition to Disease ; Glucagon/*metabolism ; Glucose Tolerance Test ; Hypoglycemic Agents/chemistry/*pharmacology/therapeutic use ; Insulin/*metabolism ; Insulysin/*antagonists & inhibitors/chemistry/genetics/metabolism ; Islet Amyloid Polypeptide/*metabolism ; Macrocyclic Compounds/chemistry/*pharmacology/therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Obesity/drug therapy/metabolism ; Signal Transduction/drug effects ; Thinness/drug therapy/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: 2015-05-07
    Description: Pluripotency, the ability to generate any cell type of the body, is an evanescent attribute of embryonic cells. Transitory pluripotent cells can be captured at different time points during embryogenesis and maintained as embryonic stem cells or epiblast stem cells in culture. Since ontogenesis is a dynamic process in both space and time, it seems counterintuitive that these two temporal states represent the full spectrum of organismal pluripotency. Here we show that by modulating culture parameters, a stem-cell type with unique spatial characteristics and distinct molecular and functional features, designated as region-selective pluripotent stem cells (rsPSCs), can be efficiently obtained from mouse embryos and primate pluripotent stem cells, including humans. The ease of culturing and editing the genome of human rsPSCs offers advantages for regenerative medicine applications. The unique ability of human rsPSCs to generate post-implantation interspecies chimaeric embryos may facilitate our understanding of early human development and evolution.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Jun -- Okamura, Daiji -- Li, Mo -- Suzuki, Keiichiro -- Luo, Chongyuan -- Ma, Li -- He, Yupeng -- Li, Zhongwei -- Benner, Chris -- Tamura, Isao -- Krause, Marie N -- Nery, Joseph R -- Du, Tingting -- Zhang, Zhuzhu -- Hishida, Tomoaki -- Takahashi, Yuta -- Aizawa, Emi -- Kim, Na Young -- Lajara, Jeronimo -- Guillen, Pedro -- Campistol, Josep M -- Esteban, Concepcion Rodriguez -- Ross, Pablo J -- Saghatelian, Alan -- Ren, Bing -- Ecker, Joseph R -- Izpisua Belmonte, Juan Carlos -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 May 21;521(7552):316-21. doi: 10.1038/nature14413. Epub 2015 May 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, California 92037, USA. ; 1] Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] The Salk Institute for Biological Studies, Genomic Analysis Laboratory, La Jolla, California 92037, USA. ; The Salk Institute for Biological Studies, Genomic Analysis Laboratory, La Jolla, California 92037, USA. ; The Salk Institute for Biological Studies, Integrated Genomics, La Jolla, California 92037, USA. ; Ludwig Institute for Cancer Research, University of California, San Diego School of Medicine, Department of Cellular and Molecular Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA. ; 1] The Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, California 92037, USA [2] Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan. ; Grado en Medicina, Universidad Catolica, San Antonio de Murcia, Campus de los Jeronimos, 135, Guadalupe 30107, Spain. ; 1] Grado en Medicina, Universidad Catolica, San Antonio de Murcia, Campus de los Jeronimos, 135, Guadalupe 30107, Spain [2] Fundacion Pedro Guillen, Clinica Cemtro, Avenida Ventisquero de la Condesa, 42, 28035 Madrid, Spain. ; Hospital Clinic of Barcelona, Carrer Villarroel, 170, 08036 Barcelona, Spain. ; University of California, Davis, Davis, California 95616, USA. ; The Salk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25945737" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Culture Techniques/methods ; Cell Line ; *Chimera ; Embryonic Stem Cells/cytology ; Female ; Germ Layers/cytology ; Humans ; Induced Pluripotent Stem Cells/cytology ; Male ; Mice ; Pan troglodytes ; Pluripotent Stem Cells/*cytology/metabolism ; Regenerative Medicine ; Species Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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