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  • 1
    Publication Date: 2010-03-06
    Description: Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841477/" 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/PMC2841477/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hirschey, Matthew D -- Shimazu, Tadahiro -- Goetzman, Eric -- Jing, Enxuan -- Schwer, Bjoern -- Lombard, David B -- Grueter, Carrie A -- Harris, Charles -- Biddinger, Sudha -- Ilkayeva, Olga R -- Stevens, Robert D -- Li, Yu -- Saha, Asish K -- Ruderman, Neil B -- Bain, James R -- Newgard, Christopher B -- Farese, Robert V Jr -- Alt, Frederick W -- Kahn, C Ronald -- Verdin, Eric -- DK019514-29/DK/NIDDK NIH HHS/ -- DK59637/DK/NIDDK NIH HHS/ -- K01 DK076573/DK/NIDDK NIH HHS/ -- K08 AG022325/AG/NIA NIH HHS/ -- K08 AG022325-01A1/AG/NIA NIH HHS/ -- P01 HL068758/HL/NHLBI NIH HHS/ -- P01 HL068758-06A1/HL/NHLBI NIH HHS/ -- P30 DK026743/DK/NIDDK NIH HHS/ -- P30 DK026743-26A1/DK/NIDDK NIH HHS/ -- R01 DK019514/DK/NIDDK NIH HHS/ -- R01 DK019514-29/DK/NIDDK NIH HHS/ -- R01 DK067509/DK/NIDDK NIH HHS/ -- R01 DK067509-04/DK/NIDDK NIH HHS/ -- U24 DK059637/DK/NIDDK NIH HHS/ -- U24 DK059637-01/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Mar 4;464(7285):121-5. doi: 10.1038/nature08778.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gladstone Institute of Virology and Immunology, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20203611" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Acyl-CoA Dehydrogenase, Long-Chain/chemistry/*metabolism ; Adenosine Triphosphate/biosynthesis/metabolism ; Adipose Tissue, Brown/enzymology/metabolism ; Animals ; Body Temperature Regulation ; Caloric Restriction ; Carnitine/analogs & derivatives/metabolism ; Cell Line ; Cold Temperature ; Fasting/metabolism ; Fatty Acids/*metabolism ; Humans ; Hypoglycemia/metabolism ; Liver/enzymology/metabolism ; Male ; Mass Spectrometry ; Mice ; Mitochondria/*enzymology/*metabolism ; Oxidation-Reduction ; Sirtuin 3/deficiency/genetics/*metabolism ; Triglycerides/metabolism ; Up-Regulation
    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: 2012-12-12
    Description: Concentrations of acetyl-coenzyme A and nicotinamide adenine dinucleotide (NAD(+)) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body d-beta-hydroxybutyrate (betaOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous betaOHB, or fasting or calorie restriction, two conditions associated with increased betaOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by betaOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with betaOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with betaOHB conferred substantial protection against oxidative stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3735349/" 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/PMC3735349/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shimazu, Tadahiro -- Hirschey, Matthew D -- Newman, John -- He, Wenjuan -- Shirakawa, Kotaro -- Le Moan, Natacha -- Grueter, Carrie A -- Lim, Hyungwook -- Saunders, Laura R -- Stevens, Robert D -- Newgard, Christopher B -- Farese, Robert V Jr -- de Cabo, Rafael -- Ulrich, Scott -- Akassoglou, Katerina -- Verdin, Eric -- P30 DK026743/DK/NIDDK NIH HHS/ -- P30 DK063720/DK/NIDDK NIH HHS/ -- R01 DK056084/DK/NIDDK NIH HHS/ -- T32 AG000212/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2013 Jan 11;339(6116):211-4. doi: 10.1126/science.1227166. Epub 2012 Dec 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23223453" target="_blank"〉PubMed〈/a〉
    Keywords: 3-Hydroxybutyric Acid/blood/*metabolism/pharmacology ; Acetylation ; Animals ; Caloric Restriction ; Catalase/metabolism ; Fasting ; Forkhead Transcription Factors/genetics ; HEK293 Cells ; Histone Deacetylase Inhibitors/blood/*metabolism/pharmacology ; Histone Deacetylases/genetics/*metabolism ; Histones/metabolism ; Humans ; Kidney/drug effects/*metabolism ; Lipid Peroxidation ; Metallothionein/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; *Oxidative Stress/genetics ; Promoter Regions, Genetic ; RNA, Small Interfering ; Superoxide Dismutase/metabolism ; Transcription, Genetic ; Transcriptional Activation
    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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  • 3
    Publication Date: 2013-09-07
    Description: The role of specific gut microbes in shaping body composition remains unclear. We transplanted fecal microbiota from adult female twin pairs discordant for obesity into germ-free mice fed low-fat mouse chow, as well as diets representing different levels of saturated fat and fruit and vegetable consumption typical of the U.S. diet. Increased total body and fat mass, as well as obesity-associated metabolic phenotypes, were transmissible with uncultured fecal communities and with their corresponding fecal bacterial culture collections. Cohousing mice harboring an obese twin's microbiota (Ob) with mice containing the lean co-twin's microbiota (Ln) prevented the development of increased body mass and obesity-associated metabolic phenotypes in Ob cage mates. Rescue correlated with invasion of specific members of Bacteroidetes from the Ln microbiota into Ob microbiota and was diet-dependent. These findings reveal transmissible, rapid, and modifiable effects of diet-by-microbiota interactions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829625/" 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/PMC3829625/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ridaura, Vanessa K -- Faith, Jeremiah J -- Rey, Federico E -- Cheng, Jiye -- Duncan, Alexis E -- Kau, Andrew L -- Griffin, Nicholas W -- Lombard, Vincent -- Henrissat, Bernard -- Bain, James R -- Muehlbauer, Michael J -- Ilkayeva, Olga -- Semenkovich, Clay F -- Funai, Katsuhiko -- Hayashi, David K -- Lyle, Barbara J -- Martini, Margaret C -- Ursell, Luke K -- Clemente, Jose C -- Van Treuren, William -- Walters, William A -- Knight, Rob -- Newgard, Christopher B -- Heath, Andrew C -- Gordon, Jeffrey I -- DK078669/DK/NIDDK NIH HHS/ -- DK58398/DK/NIDDK NIH HHS/ -- DK70977/DK/NIDDK NIH HHS/ -- F32 DK091044/DK/NIDDK NIH HHS/ -- K01 DK095774/DK/NIDDK NIH HHS/ -- K05 AA017688/AA/NIAAA NIH HHS/ -- P01 DK078669/DK/NIDDK NIH HHS/ -- P30 AG028716/AG/NIA NIH HHS/ -- P30 DK020579/DK/NIDDK NIH HHS/ -- P30 DK056341/DK/NIDDK NIH HHS/ -- P30-AG028716/AG/NIA NIH HHS/ -- R01 DK070977/DK/NIDDK NIH HHS/ -- R01 DK076729/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Sep 6;341(6150):1241214. doi: 10.1126/science.1241214.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24009397" target="_blank"〉PubMed〈/a〉
    Keywords: *Adiposity ; Adult ; Animals ; Bacteroidetes/genetics/*physiology ; Cecum/metabolism/microbiology ; Diet, Fat-Restricted ; Feces/microbiology ; Female ; Gastrointestinal Tract/*microbiology ; Germ-Free Life ; Humans ; Metabolome ; Metagenome/genetics/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Obesity/genetics/*metabolism ; Thinness/microbiology ; Twins ; Weight Gain ; Young Adult
    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: 2016-02-26
    Description: Undernourished children exhibit impaired development of their gut microbiota. Transplanting microbiota from 6- and 18-month-old healthy or undernourished Malawian donors into young germ-free mice that were fed a Malawian diet revealed that immature microbiota from undernourished infants and children transmit impaired growth phenotypes. The representation of several age-discriminatory taxa in recipient animals correlated with lean body mass gain; liver, muscle, and brain metabolism; and bone morphology. Mice were cohoused shortly after receiving microbiota from healthy or severely stunted and underweight infants; age- and growth-discriminatory taxa from the microbiota of the former were able to invade that of the latter, which prevented growth impairments in recipient animals. Adding two invasive species, Ruminococcus gnavus and Clostridium symbiosum, to the microbiota from undernourished donors also ameliorated growth and metabolic abnormalities in recipient animals. These results provide evidence that microbiota immaturity is causally related to undernutrition and reveal potential therapeutic targets and agents.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4787260/" 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/PMC4787260/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Blanton, Laura V -- Charbonneau, Mark R -- Salih, Tarek -- Barratt, Michael J -- Venkatesh, Siddarth -- Ilkaveya, Olga -- Subramanian, Sathish -- Manary, Mark J -- Trehan, Indi -- Jorgensen, Josh M -- Fan, Yue-Mei -- Henrissat, Bernard -- Leyn, Semen A -- Rodionov, Dmitry A -- Osterman, Andrei L -- Maleta, Kenneth M -- Newgard, Christopher B -- Ashorn, Per -- Dewey, Kathryn G -- Gordon, Jeffrey I -- R37 DK030292/DK/NIDDK NIH HHS/ -- T32 AI007172/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 19;351(6275). pii: aad3311. doi: 10.1126/science.aad3311.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Genome Sciences and Systems Biology and Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, MO 63108, USA. ; Sarah W. Stedman Nutrition and Metabolism Centerand Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA. ; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA. School of Public Health and Family Medicine, College of Medicine, University of Malawi, Chichiri, Blantyre 3, Malawi. ; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Paediatrics and Child Health, College of Medicine, University of Malawi, Chichiri, Blantyre 3, Malawi. ; Department of Nutrition and Program in International and Community Nutrition, University of California-Davis, Davis, CA 95616, USA. ; Department for International Health, University of Tampere School of Medicine, Tampere 33014, Finland. ; Architecture et Fonction des Macromolecules Biologiques, Centre National de la Recherche Scientifique and Aix-Marseille Universite, 13288 Marseille Cedex 9, France. Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. ; A. A. Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow 127994, Russia. ; A. A. Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow 127994, Russia. Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. ; Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. ; School of Public Health and Family Medicine, College of Medicine, University of Malawi, Chichiri, Blantyre 3, Malawi. ; Sarah W. Stedman Nutrition and Metabolism Centerand Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA. Department of Pharmacology and Cancer Biology and Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. ; Department for International Health, University of Tampere School of Medicine, Tampere 33014, Finland. Department of Pediatrics, Tampere University Hospital, Tampere 33521, Finland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912898" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacteria/*classification ; Bifidobacterium/physiology ; Body Weight ; Bone Development ; Clostridiales/physiology ; Disease Models, Animal ; Feces/microbiology ; Femur/growth & development ; Gastrointestinal Microbiome/*physiology ; Germ-Free Life ; Humans ; Infant ; Infant Nutrition Disorders/metabolism/*microbiology ; Malawi ; Male ; Mice ; Mice, Inbred C57BL
    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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