title: Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity.
abstract: The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.
authors.affiliation: University of Cambridge, Metabolic Research Laboratories, Institute of Metabolic Science Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Stefania
authors.initials: S
authors.lastname: Carobbio
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Hagen
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lelliott
authors.forename: Marc
authors.initials: M
authors.lastname: Slawik
authors.forename: Gema
authors.initials: G
authors.lastname: Medina-Gomez
authors.forename: Chong-Yew
authors.initials: CY
authors.lastname: Tan
authors.forename: Audrey
authors.initials: A
authors.lastname: Sicard
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Atherton
authors.forename: Nuria
authors.initials: N
authors.lastname: Barbarroja
authors.forename: Mikael
authors.initials: M
authors.lastname: Bjursell
authors.forename: Mohammad
authors.initials: M
authors.lastname: Bohlooly-Y
authors.forename: Sam
authors.initials: S
authors.lastname: Virtue
authors.forename: Antoinette
authors.initials: A
authors.lastname: Tuthill
authors.forename: Etienne
authors.initials: E
authors.lastname: Lefai
authors.forename: Martine
authors.initials: M
authors.lastname: Laville
authors.forename: Tingting
authors.initials: T
authors.lastname: Wu
authors.forename: Robert V
authors.initials: RV
authors.lastname: Considine
authors.forename: Hubert
authors.initials: H
authors.lastname: Vidal
authors.forename: Dominique
authors.initials: D
authors.lastname: Langin
authors.forename: Matej
authors.initials: M
authors.lastname: Oresic
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Tinahones
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Fernandez-Real
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.forename: Jaswinder K
authors.initials: JK
authors.lastname: Sethi
authors.forename: Miguel
authors.initials: M
authors.lastname: López
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
mesh_terms: D041721:3T3-L1 Cells; D000222:Adaptation, Physiological; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000503:physiopathology*; D009767:Obesity, Morbid / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*
chemical_list: C506119:Insig1 protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase
references.citation: J Lipid Res. 2002 Jun;43(6):911-20
references.pmid: 12032166
references.citation: Cell Metab. 2006 Jan;3(1):15-24
references.pmid: 16399501
references.citation: PLoS Genet. 2008 Jul 25;4(7):e1000133
references.pmid: 18654640
references.citation: Diabetologia. 2006 Mar;49(3):552-61
references.pmid: 16404553
references.citation: Horm Metab Res. 2011 Feb;43(2):77-80
references.pmid: 21120793
references.citation: Endocrinology. 2008 Nov;149(11):5432-9
references.pmid: 18635658
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9476-81
references.pmid: 12869692
references.citation: Genome Med. 2013 Apr 25;5(4):39
references.pmid: 23618465
references.citation: Diabetes. 2002 Apr;51(4):1035-41
references.pmid: 11916923
references.citation: Biochim Biophys Acta. 2002 May 3;1575(1-3):75-81
references.pmid: 12020821
references.citation: Neurosci Biobehav Rev. 2010 Sep;35(1):2-16
references.pmid: 19822172
references.citation: Biochimie. 2004 Nov;86(11):839-48
references.pmid: 15589694
references.citation: Physiol Genomics. 2009 Oct 7;39(2):109-19
references.pmid: 19602617
references.citation: J Biol Chem. 2001 Nov 30;276(48):45358-66
references.pmid: 11567032
references.citation: Diabetes. 2009 Mar;58(3):609-19
references.pmid: 19073771
references.citation: J Clin Invest. 1991 Mar;87(3):1072-81
references.pmid: 1999488
references.citation: Obes Res. 2001 Nov;9(11):706-12
references.pmid: 11707537
references.citation: J Biol Chem. 1997 Mar 14;272(11):7298-305
references.pmid: 9054427
references.citation: J Biol Chem. 2002 Sep 20;277(38):35625-34
references.pmid: 12048207
references.citation: Mol Genet Metab. 2012 Mar;105(3):421-7
references.pmid: 22209225
references.citation: J Biol Chem. 2004 Jun 4;279(23):23908-15
references.pmid: 15073165
references.citation: Diabetes. 1998 Jan;47(1):98-103
references.pmid: 9421381
references.citation: Mol Cell. 2000 Jul;6(1):77-86
references.pmid: 10949029
references.citation: J Lipid Res. 2001 Aug;42(8):1266-72
references.pmid: 11483628
references.citation: Cell. 2011 Nov 11;147(4):840-52
references.pmid: 22035958
references.citation: PLoS Genet. 2007 Apr 27;3(4):e64
references.pmid: 17465682
references.citation: Cell. 2006 Jan 13;124(1):35-46
references.pmid: 16413480
references.citation: PLoS Biol. 2011 Jun;9(6):e1000623
references.pmid: 21666801
references.citation: J Biol Chem. 2005 Jul 22;280(29):27466-76
references.pmid: 15917242
references.citation: Endocrinology. 2001 Mar;142(3):1269-77
references.pmid: 11181544
references.citation: J Lipid Res. 2006 Apr;47(4):700-4
references.pmid: 16443825
references.citation: J Clin Invest. 2007 Sep;117(9):2621-37
references.pmid: 17717599
references.citation: Biochem J. 2003 Jun 15;372(Pt 3):811-9
references.pmid: 12659631
references.citation: Diabetes. 2011 Mar;60(3):797-809
references.pmid: 21266330
references.citation: J Clin Invest. 2002 May;109(9):1125-31
references.pmid: 11994399
references.citation: Genes Dev. 2011 Jan 15;25(2):189-200
references.pmid: 21245170
references.citation: Diabetes. 2005 May;54(5):1314-23
references.pmid: 15855315
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12753-8
references.pmid: 12242332
references.citation: J Clin Endocrinol Metab. 2013 Feb;98(2):802-10
references.pmid: 23284008
references.citation: J Clin Invest. 1997 Mar 1;99(5):846-54
references.pmid: 9062341
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3155-60
references.pmid: 12624180
references.citation: J Clin Invest. 1997 Jun 15;99(12):2803-12
references.pmid: 9185499
references.citation: Am J Clin Nutr. 2008 Apr;87(4):817-23
references.pmid: 18400702
references.citation: J Biol Chem. 1998 Dec 25;273(52):35299-306
references.pmid: 9857071
references.citation: Biochim Biophys Acta. 2010 Mar;1801(3):338-49
references.pmid: 20056169