PGC-1/Spargel Counteracts High-Fat-Diet-Induced Obesity and Cardiac Lipotoxicity Downstream of TOR and Brummer ATGL Lipase

Cell Reports
Soda DiopRolf Bodmer

Abstract

Obesity and metabolic syndrome are associated with an increased risk for lipotoxic cardiomyopathy, which is strongly correlated with excessive accumulation of lipids in the heart. Obesity- and type-2-diabetes-related disorders have been linked to altered expression of the transcriptional cofactor PGC-1α, which regulates the expression of genes involved in energy metabolism. Using Drosophila, we identify PGC-1/spargel (PGC-1/srl) as a key antagonist of high-fat diet (HFD)-induced lipotoxic cardiomyopathy. We find that HFD-induced lipid accumulation and cardiac dysfunction are mimicked by reduced PGC-1/srl function and reversed by PGC-1/srl overexpression. Moreover, HFD feeding lowers PGC-1/srl expression by elevating TOR signaling and inhibiting expression of the Drosophila adipocyte triglyceride lipase (ATGL) (Brummer), both of which function as upstream modulators of PGC-1/srl. The lipogenic transcription factor SREBP also contributes to HFD-induced cardiac lipotoxicity, likely in parallel with PGC-1/srl. These results suggest a regulatory network of key metabolic genes that modulates lipotoxic heart dysfunction.

References

Apr 1, 1995·Molecular and Cellular Endocrinology·B E NoyesM H Schaffer
Aug 29, 1997·Science·D BotsteinJ M Cherry
Mar 4, 2000·Proceedings of the National Academy of Sciences of the United States of America·Y T ZhouR H Unger
Jul 29, 2000·Biochemical and Biophysical Research Communications·M GotoT Shimokawa
Feb 24, 2001·Endocrine·D York, C Bouchard
Oct 25, 2001·Proceedings of the National Academy of Sciences of the United States of America·T OsterwalderH Keshishian
May 3, 2002·Clinical and Experimental Pharmacology & Physiology·John J Lehman, Daniel P Kelly
Dec 7, 2002·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Keith BaarJohn O Holloszy
Jul 2, 2003·Proceedings of the National Academy of Sciences of the United States of America·Mary Elizabeth PattiLawrence J Mandarino
Jul 17, 2003·Endocrinology·Christina ChristoffersenLars B Nielsen
Jan 24, 2004·American Journal of Human Genetics·Rector AryaMichael P Stern
Nov 6, 2004·Gene·Ethan Bier, Rolf Bodmer
Nov 27, 2004·Nature Genetics·Robert J WessellsRolf Bodmer
Feb 15, 2005·Proceedings of the National Academy of Sciences of the United States of America·Susan J BroughtonLinda Partridge
Aug 2, 2005·Cell Metabolism·Sebastian GrönkeRonald P Kühnlein
Jan 3, 2006·Current Hypertension Reports·Nica M Borradaile, Jean E Schaffer
Jan 25, 2006·Proceedings of the National Academy of Sciences of the United States of America·Matthew J WolfHoward A Rockman
Mar 3, 2006·The Journal of Clinical Investigation·Brian N Finck, Daniel P Kelly
Jun 7, 2006·Cell Metabolism·Amit S KunteRobert B Rawson
Mar 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·Karen OcorrRolf Bodmer
Jun 15, 2007·Epidemiologic Reviews·Wenjie YangJiang He
Oct 3, 2007·Cell Metabolism·Keith D Baker, Carl S Thummel
Apr 22, 2008·The Journal of Experimental Biology·Christophe M R LeMoineChristopher D Moyes
Sep 3, 2008·Cell Metabolism·Thomas PorstmannAlmut Schulze
Sep 11, 2008·Current Opinion in Genetics & Development·Zolt Arany
Sep 18, 2009·Journal of Visualized Experiments : JoVE·Karen OcorrRolf Bodmer
Nov 17, 2009·The EMBO Journal·Stefanie K TiefenböckChristian Frei
Oct 5, 2010·Circulation Research·Glenn C RoweZolt Arany
Oct 5, 2010·Journal of Molecular and Cellular Cardiology·Joel Schilling, Daniel P Kelly
Oct 12, 2010·Biochimica Et Biophysica Acta·Richard C Scarpulla
Jan 12, 2011·Hypertension·Yingmei Zhang, Jun Ren
Jan 29, 2011·Journal of Biomedicine & Biotechnology·Keizo Kanasaki, Daisuke Koya
Aug 23, 2011·Nature Medicine·Guenter HaemmerleRudolf Zechner
Nov 4, 2011·Trends in Endocrinology and Metabolism : TEM·Ian S Patten, Zolt Arany
Nov 8, 2011·Cell Metabolism·Michael ReraDavid W Walker
Feb 7, 2012·Journal of Cellular and Molecular Medicine·Soda Balla Diop, Rolf Bodmer
Dec 5, 2012·PLoS Genetics·Véronique MonnierLaurent Perrin
Jan 18, 2013·PLoS Genetics·Jianbo NaRoss Cagan

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Citations

Dec 22, 2015·Molecular and Cellular Endocrinology·Rita T Brookheart, Jennifer G Duncan
Sep 27, 2015·Cardiovascular Diabetology·Nathan W RobertsAhlke Heydemann
Jun 11, 2015·The Journal of Physiology·Leah Cannon, Rolf Bodmer
Jun 3, 2016·International Journal of Cardiology·Tomasz A BondaKarol A Kamiński
Jul 28, 2016·Reproduction : the Official Journal of the Society for the Study of Fertility·Rita T Brookheart, Jennifer G Duncan
Oct 21, 2015·Trends in Endocrinology and Metabolism : TEM·Soda Balla Diop, Rolf Bodmer
Oct 6, 2016·Mechanisms of Development·Juan Manuel Murillo-Maldonado, Juan Rafael Riesgo-Escovar
Sep 9, 2016·Disease Models & Mechanisms·Susumu Hirabayashi
Jun 30, 2018·International Journal of Molecular Sciences·Martina Gáliková, Peter Klepsatel
Oct 13, 2018·Annual Review of Entomology·Sheng LiQili Feng
Sep 17, 2017·Molecular Systems Biology·Luke S TainLinda Partridge
Jul 3, 2015·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Christopher M HardyAllen G Gibbs
May 27, 2016·Médecine sciences : M/S·Laurent Perrin, Laurence Röder
Mar 9, 2018·The Journal of Experimental Biology·Laura Palanker Musselman, Ronald P Kühnlein
Feb 18, 2016·Journal of Cardiovascular Development and Disease·Ouarda Taghli-LamallemKrzysztof Jagla
Aug 24, 2018·International Journal of Molecular Sciences·Yitao XuJunmei Ye
Sep 11, 2020·Molecular Biology Reports·Iuliia Iu MazurIldus I Ahmetov
Mar 16, 2019·Scientific Reports·Robert P J CormierNicolas Pichaud
Jan 16, 2019·Nature Communications·Maria Clara GuidaRolf Bodmer
Jun 30, 2019·Developmental Biology·Mohammed Abul BasarAtanu Duttaroy
Feb 25, 2021·Insect Biochemistry and Molecular Biology·Robert J CormierNicolas Pichaud
Mar 16, 2021·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Christoph HeierOleh Lushchak
Aug 24, 2021·The Journal of Experimental Biology·Bryon F Tuthill IiLaura Palanker Musselman
Jan 4, 2022·Pflügers Archiv : European journal of physiology·Carolina Jaquenod De GiustiAlicia Mattiazzi

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