title: Downregulation of the acetyl-CoA metabolic network in adipose tissue of obese diabetic individuals and recovery after weight loss.
abstract: OBJECTIVE
  Not all obese individuals develop type 2 diabetes. Why some obese individuals retain normal glucose tolerance (NGT) is not well understood. We hypothesise that the biochemical mechanisms that underlie the function of adipose tissue can help explain the difference between obese individuals with NGT and those with type 2 diabetes.
  
  
  METHODS
  RNA sequencing was used to analyse the transcriptome of samples extracted from visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of obese women with NGT or type 2 diabetes who were undergoing bariatric surgery. The gene expression data was analysed by bioinformatic visualisation and statistical analyses techniques.
  
  
  RESULTS
  A network-based approach to distinguish obese individuals with NGT from obese individuals with type 2 diabetes identified acetyl-CoA metabolic network downregulation as an important feature in the pathophysiology of type 2 diabetes in obese individuals. In general, genes within two reaction steps of acetyl-CoA were found to be downregulated in the VAT and SAT of individuals with type 2 diabetes. Upon weight loss and amelioration of metabolic abnormalities three months following bariatric surgery, the expression level of these genes recovered to levels seen in individuals with NGT. We report four novel genes associated with type 2 diabetes and recovery upon weight loss: ACAT1 (encoding acetyl-CoA acetyltransferase 1), ACACA (encoding acetyl-CoA carboxylase α), ALDH6A1 (encoding aldehyde dehydrogenase 6 family, member A1) and MTHFD1 (encoding methylenetetrahydrofolate dehydrogenase).
  
  
  CONCLUSIONS
  Downregulation of the acetyl-CoA network in VAT and SAT is an important feature in the pathophysiology of type 2 diabetes in obese individuals. ACAT1, ACACA, ALDH6A1 and MTHFD1 represent novel biomarkers in adipose tissue associated with type 2 diabetes in obese individuals.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, P.O. Box 9600, 2300 RC, Leiden, the Netherlands.
authors.forename: Harish
authors.initials: H
authors.lastname: Dharuri
authors.forename: Peter A C
authors.initials: PA
authors.lastname: 't Hoen
authors.forename: Jan B
authors.initials: JB
authors.lastname: van Klinken
authors.forename: Peter
authors.initials: P
authors.lastname: Henneman
authors.forename: Jeroen F J
authors.initials: JF
authors.lastname: Laros
authors.forename: Mirjam A
authors.initials: MA
authors.lastname: Lips
authors.forename: Fatiha
authors.initials: F
authors.lastname: El Bouazzaoui
authors.forename: Gert-Jan B
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: Ignace
authors.initials: I
authors.lastname: Janssen
authors.forename: Bert
authors.initials: B
authors.lastname: van Ramshorst
authors.forename: Bert A
authors.initials: BA
authors.lastname: van Wagensveld
authors.forename: Hanno
authors.initials: H
authors.lastname: Pijl
authors.forename: Ko
authors.initials: K
authors.lastname: Willems van Dijk
authors.forename: Vanessa
authors.initials: V
authors.lastname: van Harmelen
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics; D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D050152:Intra-Abdominal Fat / Q000378:metabolism; D008297:Male; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009765:Obesity / Q000201:enzymology* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015431:Weight Loss / Q000502:physiology
chemical_list: D015778:Minor Histocompatibility Antigens; D000105:Acetyl Coenzyme A; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase
references.citation: Diabetes. 2006 Jun;55(6):1792-9
references.pmid: 16731844
references.citation: Nature. 2006 Dec 14;444(7121):875-80
references.pmid: 17167476
references.citation: Curr Opin Endocrinol Diabetes Obes. 2012 Oct;19(5):341-6
references.pmid: 22895358
references.citation: PLoS Genet. 2007 Jun;3(6):e96
references.pmid: 17571924
references.citation: J Clin Endocrinol Metab. 2005 Jul;90(7):4145-50
references.pmid: 15855252
references.citation: Biochemistry. 2007 Apr 10;46(14):4305-21
references.pmid: 17371050
references.citation: Diabetes. 2013 Mar;62(3):855-63
references.pmid: 23223024
references.citation: Cold Spring Harb Symp Quant Biol. 2011;76:195-202
references.pmid: 21900151
references.citation: Nature. 2013 Sep 26;501(7468):506-11
references.pmid: 24037378
references.citation: Diabetes Care. 2003 Mar;26(3):725-31
references.pmid: 12610029
references.citation: BMC Med Genomics. 2010 Aug 05;3:34
references.pmid: 20687939
references.citation: J Biol Chem. 2010 Apr 9;285(15):11348-56
references.pmid: 20093359
references.citation: Diabetologia. 2014 Jan;57(1):167-76
references.pmid: 24100782
references.citation: JAMA. 2003 Jan 1;289(1):76-9
references.pmid: 12503980
references.citation: BMC Public Health. 2011 Oct 01;11:754
references.pmid: 21962038
references.citation: Nat Rev Endocrinol. 2013 Jan;9(1):13-27
references.pmid: 23165161
references.citation: J Clin Endocrinol Metab. 2011 Jan;96(1):E73-82
references.pmid: 21047918
references.citation: Nat Genet. 2011 Feb;43(2):117-20
references.pmid: 21186350
references.citation: Mol Biosyst. 2012 Oct;8(10):2545-58
references.pmid: 22699794
references.citation: Trends Endocrinol Metab. 2010 Feb;21(2):75-82
references.pmid: 19819719
references.citation: Circ Res. 2012 Jul 20;111(3):359-74
references.pmid: 22821909
references.citation: Br J Cancer. 2010 May 11;102(10):1541-8
references.pmid: 20407445
references.citation: Int J Obes Relat Metab Disord. 1997 Nov;21(11):972-9
references.pmid: 9368819
references.citation: Nat Rev Genet. 2011 Jan;12(1):56-68
references.pmid: 21164525
references.citation: Mol Cell. 2011 May 20;42(4):426-37
references.pmid: 21596309
references.citation: Nat Biotechnol. 2013 Nov;31(11):1015-22
references.pmid: 24037425
references.citation: J Clin Endocrinol Metab. 2013 Oct;98(10):E1610-9
references.pmid: 23979951
references.citation: Nat Biotechnol. 2013 May;31(5):419-25
references.pmid: 23455439
references.citation: Nat Rev Genet. 2009 Jan;10(1):57-63
references.pmid: 19015660
references.citation: PLoS One. 2010 May 18;5(5):e10693
references.pmid: 20502693
references.citation: Nat Rev Genet. 2011 Feb;12(2):87-98
references.pmid: 21191423
references.citation: Bioinformatics. 2004 Jan 1;20(1):93-9
references.pmid: 14693814
references.citation: Nat Methods. 2008 Jul;5(7):621-8
references.pmid: 18516045
references.citation: Best Pract Res Clin Endocrinol Metab. 2013 Apr;27(2):163-77
references.pmid: 23731879
references.citation: BMC Med Genomics. 2012 Apr 03;5:9
references.pmid: 22471940
references.citation: Diabetologia. 2011 Apr;54(4):864-8
references.pmid: 21174075