Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest).

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Adipose Tissue/*cytology ; Adipose Tissue/*metabolism ; Diet, High-Fat/*adverse effects ; Proteins/*metabolism; Adipogenesis/drug effects ; Adipose Tissue/drug effects ; Animals ; Gene Knockout Techniques ; Glucose Tolerance Test ; Insulin Resistance ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/drug effects ; Mice ; Proteins/genetics

Interindividual variation of white adipose tissue (WAT) expression of mesoderm specific transcript (Mest), a paternally-expressed imprinted gene belonging to the α/β-hydrolase fold protein family, becomes apparent among genetically inbred mice fed high fat diet (HFD) and is positively associated with adipose tissue expansion (ATE). To elucidate a role for MEST in ATE, mice were developed with global and adipose tissue inactivation of Mest. Mice with homozygous (MestgKO) and paternal allelic (MestpKO) inactivation of Mest were born at expected Mendelian frequencies, showed no behavioral or physical abnormalities, and did not perturb expression of the Mest locus-derived microRNA miR-335. MestpKO mice fed HFD showed reduced ATE and adipocyte hypertrophy, improved glucose tolerance, and reduced WAT expression of genes associated with hypoxia and inflammation compared to littermate controls. Remarkably, caloric intake and energy expenditure were unchanged between genotypes. Mice with adipose tissue inactivation of Mest were phenotypically similar to MestpKO, supporting a role for WAT MEST in ATE. Global profiling of WAT gene expression of HFD-fed control and MestpKO mice detected few differences between genotypes; nevertheless, genes with reduced expression in MestpKO mice were associated with immune processes and consistent with improved glucose homeostasis. Ear-derived mesenchymal stem cells (EMSC) from MestgKO mice showed no differences in adipogenic differentiation compared to control cells unless challenged by shRNA knockdown of Gpat4, an enzyme that mediates lipid accumulation in adipocytes. Reduced adipogenic capacity of EMSC from MestgKO after Gpat4 knockdown suggests that MEST facilitates lipid accumulation in adipocytes. Our data suggests that reduced diet-induced ATE in MEST-deficient mice diminishes hypoxia and inflammation in WAT leading to improved glucose tolerance and insulin sensitivity. Since inactivation of Mest in mice has minimal additional effects aside from reduction of ATE, an intervention that mitigates MEST function in adipocytes is a plausible strategy to obviate obesity and type-2-diabetes.

Biochem Biophys Res Commun. 2009 Aug 7;385(4):492-6. (PMID: 19460359)
EMBO J. 1997 Nov 3;16(21):6510-20. (PMID: 9351832)
Genes Dev. 2000 Apr 15;14(8):963-80. (PMID: 10783168)
Genes Nutr. 2015 Sep;10(5):477. (PMID: 26143179)
Diabetes. 2013 Apr;62(4):1320-8. (PMID: 23209187)
J Biol Chem. 2004 Aug 13;279(33):35017-24. (PMID: 15180999)
J Clin Invest. 2013 Jan;123(1):215-23. (PMID: 23221344)
Int J Obes (Lond). 2015 Apr;39(4):650-7. (PMID: 24158121)
Am J Physiol Heart Circ Physiol. 2006 Jan;290(1):H55-63. (PMID: 16113065)
FASEB J. 2008 Nov;22(11):3925-37. (PMID: 18644838)
N Engl J Med. 1990 May 24;322(21):1483-7. (PMID: 2336075)
Curr Protein Pept Sci. 2000 Sep;1(2):209-35. (PMID: 12369917)
PLoS Genet. 2006 May;2(5):e81. (PMID: 16733553)
Diabetes. 2015 Apr;64(4):1235-48. (PMID: 25352637)
Nature. 1988 Apr 7;332(6164):564-8. (PMID: 3282170)
Nature. 2006 Dec 14;444(7121):847-53. (PMID: 17167472)
J Lipid Res. 2009 Apr;50 Suppl:S52-6. (PMID: 18952572)
Cell Metab. 2016 Jun 14;23 (6):1216-23. (PMID: 27304513)
Proc Natl Acad Sci U S A. 2002 May 14;99(10):6567-72. (PMID: 12011421)
PLoS One. 2015 Dec 23;10(12):e0145342. (PMID: 26699615)
PLoS One. 2015 Jun 22;10(6):e0130436. (PMID: 26098312)
Front Pharmacol. 2016 Jan 21;6:309. (PMID: 26834634)
Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5860-5. (PMID: 8650183)
Biochem J. 2011 Jun 1;436(2):263-9. (PMID: 21375506)
J Lipid Res. 2006 Apr;47(4):745-54. (PMID: 16436371)
J Biol Chem. 2014 Jun 27;289(26):18478-88. (PMID: 24808178)
Arch Biochem Biophys. 2005 Apr 15;436(2):276-84. (PMID: 15797240)
Am J Clin Nutr. 2010 Jan;91(1):184-90. (PMID: 19812171)
Stem Cells Dev. 2010 Dec;19(12 ):1863-73. (PMID: 20412023)
Am J Physiol Renal Physiol. 2002 May;282(5):F953-65. (PMID: 11934706)
PLoS One. 2010 Jun 21;5(6):e11015. (PMID: 20574519)
Nat Genet. 1995 Sep;11(1):52-9. (PMID: 7550314)
Endocrinology. 2003 Nov;144(11):4773-82. (PMID: 12960083)
Appl Physiol Nutr Metab. 2014 Aug;39(8):895-901. (PMID: 24844367)
J Cell Biol. 2015 Mar 2;208(5):501-12. (PMID: 25733711)
Mol Cell Biol. 2014 Mar;34(6):1170-86. (PMID: 24421389)
Biochimie. 2016 May;124:134-40. (PMID: 26005096)
J Endocrinol. 2010 Dec;207(3):245-55. (PMID: 20870709)
Am J Physiol Endocrinol Metab. 2005 Jan;288(1):E117-24. (PMID: 15353408)
Stem Cells Dev. 2016 Jul 15;25(14):1084-94. (PMID: 27224420)
Obesity (Silver Spring). 2014 Oct;22(10):2147-55. (PMID: 24942674)
J Lipid Res. 2014 Oct;55(10):2124-36. (PMID: 25114171)
Hum Mol Genet. 1997 Oct;6(11):1907-15. (PMID: 9302270)
Drug Discov Today Dis Models. 2007;4(1):17-24. (PMID: 18193096)
Arch Toxicol. 2009 Apr;83(4):297-318. (PMID: 19340413)
Diabetes. 2009 Jan;58(1):203-8. (PMID: 18952834)
J Biol Chem. 2008 Apr 11;283(15):10048-57. (PMID: 18238778)
Protein Pept Lett. 2012 Feb;19(2):132-43. (PMID: 21933125)
J Biol Chem. 2002 Sep 20;277(38):35105-12. (PMID: 12124379)
J Pharmacol Exp Ther. 2005 Jul;314(1):260-70. (PMID: 15798002)
Protein Eng. 1992 Apr;5(3):197-211. (PMID: 1409539)
FEBS Lett. 2007 Jan 9;581(1):91-6. (PMID: 17182038)
Exp Clin Endocrinol Diabetes. 2009 Jun;117(6):241-50. (PMID: 19358089)
J Bone Miner Res. 2014 Jul;29(7):1575-85. (PMID: 24347469)
Nat Genet. 1998 Oct;20(2):163-9. (PMID: 9771709)
Science. 2000 Aug 11;289(5481):950-3. (PMID: 10937998)
PLoS One. 2012;7(6):e38979. (PMID: 22723914)
N Engl J Med. 1990 May 24;322(21):1477-82. (PMID: 2336074)
Genesis. 2004 Feb;38(2):51-7. (PMID: 14994267)
Biochimie. 2016 May;124:124-33. (PMID: 26001362)
Dev Cell. 2013 Feb 25;24(4):384-99. (PMID: 23415954)
FASEB J. 2005 Jul;19(9):1205-7. (PMID: 15857881)
Am J Clin Nutr. 2010 Jan;91(1):5-6. (PMID: 19939981)
Metabolism. 2004 Jun;53(6):799-808. (PMID: 15164332)
Cell Biochem Biophys. 2014 Mar;68(2):283-90. (PMID: 23801157)
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21. (PMID: 11309499)
Am J Physiol Cell Physiol. 2007 Mar;292(3):C996-1012. (PMID: 16987999)
Hepatology. 2009 Aug;50(2):434-42. (PMID: 19472314)
Nature. 2015 Feb 12;518(7538):197-206. (PMID: 25673413)
Am J Physiol Endocrinol Metab. 2002 Apr;282(4):E834-42. (PMID: 11882503)
Trends Endocrinol Metab. 2009 Jan;20(1):16-24. (PMID: 19008118)
Nat Genet. 2003 Mar;33 Suppl:245-54. (PMID: 12610534)
Nucleic Acids Res. 2013 Jan;41(Database issue):D423-9. (PMID: 23193256)
PLoS One. 2012;7(2):e30392. (PMID: 22383960)
Ann N Y Acad Sci. 2016 Jan;1363:50-8. (PMID: 26647164)
J Reprod Dev. 2012;58(4):490-500. (PMID: 22522229)
Am J Clin Nutr. 2006 Nov;84(5):1033-42. (PMID: 17093155)
Int J Obes (Lond). 2015 Dec;39(12):1733-41. (PMID: 26119994)
J Biol Chem. 2001 Sep 7;276(36):34167-74. (PMID: 11445576)
J Biol Chem. 2004 Dec 3;279(49):50743-53. (PMID: 15377667)
Int J Clin Exp Pathol. 2010 Mar 25;3(5):505-14. (PMID: 20606731)
J Lipid Res. 2006 Apr;47(4):734-44. (PMID: 16449762)

P30 GM106391 United States GM NIGMS NIH HHS; P30 DK072476 United States DK NIDDK NIH HHS; R01 DK090361 United States DK NIDDK NIH HHS; P20 GM103528 United States GM NIGMS NIH HHS; P30 GM103392 United States GM NIGMS NIH HHS

0 (Proteins)
0 (mesoderm specific transcript protein)

Date Created: 20170623 Date Completed: 20170918 Latest Revision: 20230804

20231215

PMC5481029

10.1371/journal.pone.0179879

28640866