title: Genetic ablation of calcium-independent phospholipase A2gamma prevents obesity and insulin resistance during high fat feeding by mitochondrial uncoupling and increased adipocyte fatty acid oxidation.
abstract: Phospholipases are critical enzyme mediators participating in many aspects of cellular function through modulating the generation of lipid 2nd messengers, membrane physical properties, and cellular bioenergetics. Here, we demonstrate that mice null for calcium-independent phospholipase A(2)γ (iPLA(2)γ(-/-)) are completely resistant to high fat diet-induced weight gain, adipocyte hypertrophy, hyperinsulinemia, and insulin resistance, which occur in iPLA(2)γ(+/+) mice after high fat feeding. Notably, iPLA(2)γ(-/-) mice were lean, demonstrated abdominal lipodystrophy, and remained insulin-sensitive despite having a marked impairment in glucose-stimulated insulin secretion after high fat feeding. Respirometry of adipocyte explants from iPLA(2)γ(-/-) mice identified increased rates of oxidation of multiple different substrates in comparison with adipocyte explants from wild-type littermates. Shotgun lipidomics of adipose tissue from wild-type mice demonstrated the anticipated 2-fold increase in triglyceride content after high fat feeding. In sharp contrast, the adipocyte triglyceride content was identical in iPLA(2)γ(-/-) mice fed either a standard diet or a high fat diet. Respirometry of skeletal muscle mitochondria from iPLA(2)γ(-/-) mice demonstrated marked decreases in state 3 respiration using multiple substrates whose metabolism was uncoupled from ATP production. Shotgun lipidomics of skeletal muscle revealed a decreased content of cardiolipin with an altered molecular species composition thereby identifying the mechanism underlying mitochondrial uncoupling in the iPLA(2)γ(-/-) mouse. Collectively, these results identify iPLA(2)γ as an obligatory upstream enzyme that is necessary for efficient electron transport chain coupling and energy production through its participation in the alterations of cellular bioenergetics that promote the development of the metabolic syndrome.
authors.affiliation: Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mancuso
authors.forename: Harold F
authors.initials: HF
authors.lastname: Sims
authors.forename: Kui
authors.initials: K
authors.lastname: Yang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kiebish
authors.forename: Xiong
authors.initials: X
authors.lastname: Su
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jenkins
authors.forename: Shaoping
authors.initials: S
authors.lastname: Guan
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Moon
authors.forename: Terri
authors.initials: T
authors.lastname: Pietka
authors.forename: Fatiha
authors.initials: F
authors.lastname: Nassir
authors.forename: Timothy
authors.initials: T
authors.lastname: Schappe
authors.forename: Kristin
authors.initials: K
authors.lastname: Moore
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.forename: Nada A
authors.initials: NA
authors.lastname: Abumrad
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001823:Body Composition; D002118:Calcium / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage*; D004734:Energy Metabolism; D005227:Fatty Acids / Q000737:chemistry* / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009765:Obesity / Q000517:prevention & control*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D007328:Insulin; D012333:RNA, Messenger; D014280:Triglycerides; D054513:Group IV Phospholipases A2; D002118:Calcium
references.citation: Am J Physiol Cell Physiol. 2010 Apr;298(4):C921-8
references.pmid: 20107045
references.citation: J Biol Chem. 2006 Aug 4;281(31):22275-22288
references.pmid: 16728389
references.citation: Methods Mol Biol. 2001;155:295-303
references.pmid: 11293080
references.citation: Diabetes. 2004 Feb;53 Suppl 1:S179-85
references.pmid: 14749285
references.citation: Rapid Commun Mass Spectrom. 2008 Jul;22(13):2115-24
references.pmid: 18523984
references.citation: J Biol Chem. 2004 May 21;279(21):21740-8
references.pmid: 15024020
references.citation: J Appl Physiol (1985). 2009 Apr;106(4):1425-34
references.pmid: 19179648
references.citation: J Inherit Metab Dis. 1994;17(4):470-86
references.pmid: 7967497
references.citation: J Biol Chem. 1991 Aug 5;266(22):14526-34
references.pmid: 1860859
references.citation: Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E223-30
references.pmid: 16926382
references.citation: J Biol Chem. 1990 Jun 25;265(18):10622-30
references.pmid: 2355013
references.citation: Anal Chem. 2009 Jun 1;81(11):4356-68
references.pmid: 19408941
references.citation: Diabetes Care. 2009 Apr;32(4):677-9
references.pmid: 19131470
references.citation: Curr Opin Lipidol. 2009 Feb;20(1):50-6
references.pmid: 19133412
references.citation: J Biol Chem. 2009 May 29;284(22):14809-18
references.pmid: 19332540
references.citation: Biochemistry. 1993 May 25;32(20):5339-51
references.pmid: 8499439
references.citation: Eur J Biochem. 2004 Dec;271(23-24):4709-24
references.pmid: 15606758
references.citation: Am J Physiol Renal Physiol. 2007 Feb;292(2):F853-60
references.pmid: 17047165
references.citation: Annu Rev Biochem. 2006;75:295-332
references.pmid: 16756494
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2337-41
references.pmid: 19164547
references.citation: Biochem J. 2002 Feb 15;362(Pt 1):23-32
references.pmid: 11829736
references.citation: Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1097-114
references.pmid: 20179248
references.citation: Proteomics. 2008 Jun;8(12):2556-72
references.pmid: 18563753
references.citation: Curr Diab Rep. 2008 Jun;8(3):185-91
references.pmid: 18625114
references.citation: Nature. 2006 Dec 14;444(7121):881-7
references.pmid: 17167477
references.citation: J Biol Chem. 2009 Oct 16;284(42):29230-9
references.pmid: 19700766
references.citation: J Clin Invest. 2004 Nov;114(9):1281-9
references.pmid: 15520860
references.citation: Expert Rev Proteomics. 2005 Apr;2(2):253-64
references.pmid: 15892569
references.citation: J Neurochem. 2005 Aug;94(4):980-94
references.pmid: 16092941
references.citation: J Biol Chem. 2007 Nov 30;282(48):34611-22
references.pmid: 17923475
references.citation: J Clin Invest. 2005 Mar;115(3):547-55
references.pmid: 15765136
references.citation: J Biol Chem. 2005 Jul 22;280(29):26669-79
references.pmid: 15908428
references.citation: Med Res Rev. 2005 Jan;25(1):49-65
references.pmid: 15389734
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3444-9
references.pmid: 16492734
references.citation: J Biol Chem. 2006 Jan 6;281(1):187-98
references.pmid: 16286468
references.citation: Mol Endocrinol. 2005 Feb;19(2):504-15
references.pmid: 15471944
references.citation: J Lipid Res. 2003 Sep;44(9):1795-801
references.pmid: 12777477
references.citation: J Biol Chem. 2006 Mar 17;281(11):6931-9
references.pmid: 16407316
references.citation: Diabetes. 2007 Jul;56(7):1872-80
references.pmid: 17440173
references.citation: Biochemistry. 2007 May 29;46(21):6417-28
references.pmid: 17487985
references.citation: Comp Biochem Physiol A Mol Integr Physiol. 2004 Feb;137(2):435-46
references.pmid: 15123217
references.citation: J Biol Chem. 2006 Jul 28;281(30):20958-20973
references.pmid: 16732058
references.citation: J Clin Invest. 2002 May;109(10):1381-9
references.pmid: 12021254
references.citation: Biochemistry. 1993 Jan 12;32(1):327-36
references.pmid: 8418853
references.citation: J Biol Chem. 2008 May 23;283(21):14317-26
references.pmid: 18308721
references.citation: J Lipid Res. 2009 Feb;50(2):225-32
references.pmid: 18776171
references.citation: J Biol Chem. 2000 Apr 7;275(14):9937-45
references.pmid: 10744668
references.citation: J Biol Chem. 2004 Nov 19;279(47):48968-75
references.pmid: 15364929
references.citation: J Biol Chem. 2005 Aug 19;280(33):29403-8
references.pmid: 15972817
references.citation: Biochemistry. 1993 Jan 12;32(1):337-46
references.pmid: 8418854
references.citation: Anal Biochem. 2004 Jul 15;330(2):317-31
references.pmid: 15203339
references.citation: Am J Physiol Endocrinol Metab. 2008 Feb;294(2):E217-29
references.pmid: 17895289
references.citation: PLoS Comput Biol. 2009 Mar;5(3):e1000324
references.pmid: 19325873
references.citation: Diabetes. 2010 Feb;59(2):448-59
references.pmid: 19903739
references.citation: J Biol Chem. 2007 Jul 6;282(27):19493-501
references.pmid: 17507371
references.citation: Biochemistry. 2004 Dec 14;43(49):15584-94
references.pmid: 15581371
references.citation: J Clin Invest. 2007 Sep;117(9):2539-52
references.pmid: 17694178
references.citation: J Biol Chem. 2002 Sep 6;277(36):32807-14
references.pmid: 12089145
references.citation: J Biol Chem. 2002 Nov 15;277(46):43553-6
references.pmid: 12364341
references.citation: Annu Rev Biochem. 2006;75:367-401
references.pmid: 16756496
references.citation: J Lipid Res. 2006 Apr;47(4):864-79
references.pmid: 16449763
references.citation: Annu Rev Med. 2005;56:45-62
references.pmid: 15660501