title: Genetic defect in phospholipase Cδ1 protects mice from obesity by regulating thermogenesis and adipogenesis.
abstract: OBJECTIVE
  Regulation of obesity development is an important issue to prevent metabolic syndromes. Gene-disrupted mice of phospholipase Cδ1 (PLCδ1), a key enzyme of phosphoinositide turnover, seemed to show leanness. Here we examined whether and how PLCδ1 is involved in obesity.
  
  
  METHODS
  Weight gain, insulin sensitivity, and metabolic rate in PLCδ1(-/-) mice were compared with PLCδ1(+/-) littermate mice on a high-fat diet. Thermogenic and adipogenetic potentials of PLCδ1(-/-) immortalized brown adipocytes and adipogenesis of PLCδ1-knockdown (KD) 3T3L1 cells, or PLCδ1(-/-) white adipose tissue (WAT) stromal-vascular fraction (SVF) cells, were also investigated.
  
  
  RESULTS
  PLCδ1(-/-) mice showed marked decreases in weight gain and mass of epididymal WAT and preserved insulin sensitivity compared with PLCδ1(+/-) mice on a high-fat diet. In addition, PLCδ1(-/-) mice have a higher metabolic rate such as higher oxygen consumption and heat production. When control immortalized brown adipocytes were treated with thermogenic inducers, expression of PLCδ1 was decreased and thermogenic gene uncoupling protein 1 (UCP1) was upregulated to a greater extent in PLCδ1(-/-) immortalized brown adipocytes. In contrast, ectopic expression of PLCδ1 in PLCδ1(-/-) brown adipocytes induced a decrease in UCP expression, indicating that PLCδ1 negatively regulates thermogenesis. Importantly, accumulation of lipid droplets was severely decreased when PLCδ1-KD 3T3L1 cells, or PLCδ1(-/-) WAT SVF cells, were differentiated, whereas differentiation of PLCδ1(-/-) brown preadipocytes was promoted.
  
  
  CONCLUSIONS
  PLCδ1 has essential roles in thermogenesis and adipogenesis and thereby contributes to the development of obesity.
authors: Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
authors: Masayuki
authors: M
authors: Hirata
authors: Mutsumi
authors: M
authors: Suzuki
authors: Rika
authors: R
authors: Ishii
authors: Reiko
authors: R
authors: Satow
authors: Takafumi
authors: T
authors: Uchida
authors: Tomoya
authors: T
authors: Kitazumi
authors: Tsutomu
authors: T
authors: Sasaki
authors: Tadahiro
authors: T
authors: Kitamura
authors: Hideki
authors: H
authors: Yamaguchi
authors: Yoshikazu
authors: Y
authors: Nakamura
authors: Kiyoko
authors: K
authors: Fukami
references: Biochem Biophys Res Commun. 2007 May 18;356(4):912-8
references: 17397799
references: J Clin Invest. 2004 Oct;114(7):928-36
references: 15467831
references: Cancer Res. 2007 Nov 15;67(22):10720-6
references: 18006814
references: Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E999-E1003
references: 19622783
references: Cell Metab. 2009 Feb;9(2):203-9
references: 19187776
references: Nature. 2008 Aug 21;454(7207):1000-4
references: 18719589
references: J Clin Invest. 2006 Jul;116(7):1784-92
references: 16823476
references: Biochem J. 1998 Aug 1;333 ( Pt 3):719-27
references: 9677333
references: Prog Lipid Res. 2010 Oct;49(4):429-37
references: 20553968
references: Hepatology. 2009 May;49(5):1525-36
references: 19296465
references: J Biol Chem. 2008 Jul 25;283(30):21220-9
references: 18445590
references: Cell Metab. 2010 Apr 7;11(4):257-62
references: 20374957
references: Mol Cell Endocrinol. 2010 Apr 29;318(1-2):10-4
references: 19733624
references: Genes Dev. 2008 May 15;22(10):1269-75
references: 18483216
references: Diabetes. 2011 Jan;60(1):17-23
references: 21193735
references: J Clin Invest. 2001 Nov;108(9):1379-85
references: 11696583
references: Int J Biochem Cell Biol. 2006;38(12):2151-63
references: 16950644
references: Curr Opin Cell Biol. 2001 Aug;13(4):493-9
references: 11454457
references: Mol Cell Endocrinol. 2010 Apr 29;318(1-2):69-78
references: 19948207
references: BMB Rep. 2008 Jun 30;41(6):415-34
references: 18593525
references: FASEB J. 2008 Mar;22(3):841-9
references: 17938256
references: Trends Endocrinol Metab. 2009 Apr;20(3):107-14
references: 19269847
references: EMBO J. 2003 Jun 16;22(12):2981-91
references: 12805213
references: Cell. 1998 Mar 20;92(6):829-39
references: 9529258
references: Cell Metab. 2010 Apr 7;11(4):253-6
references: 20374956
references: Cell. 2001 Feb 23;104(4):517-29
references: 11239409
references: Cell. 2009 Sep 4;138(5):961-75
references: 19737522
references: Int J Obes (Lond). 2008 Dec;32 Suppl 7:S32-8
references: 19136989
references: Cell Metab. 2008 Dec;8(6):454-7
references: 19041761
references: Nature. 2006 Oct 12;443(7112):651-7
references: 17035995
references: Mol Cell Biol. 1999 Jun;19(6):4008-18
references: 10330141
references: Nature. 2006 Dec 14;444(7121):847-53
references: 17167472
references: Cell Metab. 2007 Oct;6(4):320-8
references: 17908560
references: Cell. 2008 Oct 17;135(2):240-9
references: 18835024
references: Cell Metab. 2010 Apr 7;11(4):248-52
references: 20374955
references: Nature. 1997 May 1;387(6628):90-4
references: 9139827
references: J Biol Chem. 1999 Dec 3;274(49):34795-802
references: 10574950
references: Exp Hematol. 2003 Nov;31(11):1007-14
references: 14585362
references: J Biol Chem. 2005 Apr 1;280(13):12867-75
references: 15664998
references: Mol Cell Biol. 2006 Oct;26(20):7372-87
references: 16908540
references: Biochim Biophys Acta. 2011 Apr;1812(4):495-506
references: 21236337
references: Cancer Res. 2009 Nov 15;69(22):8594-602
references: 19887621