title: Syndecan-1 is required to maintain intradermal fat and prevent cold stress.
abstract: Homeostatic temperature regulation is fundamental to mammalian physiology and is controlled by acute and chronic responses of local, endocrine and nervous regulators. Here, we report that loss of the heparan sulfate proteoglycan, syndecan-1, causes a profoundly depleted intradermal fat layer, which provides crucial thermogenic insulation for mammals. Mice without syndecan-1 enter torpor upon fasting and show multiple indicators of cold stress, including activation of the stress checkpoint p38α in brown adipose tissue, liver and lung. The metabolic phenotype in mutant mice, including reduced liver glycogen, is rescued by housing at thermoneutrality, suggesting that reduced insulation in cool temperatures underlies the observed phenotypes. We find that syndecan-1, which functions as a facultative lipoprotein uptake receptor, is required for adipocyte differentiation in vitro. Intradermal fat shows highly dynamic differentiation, continuously expanding and involuting in response to hair cycle and ambient temperature. This physiology probably confers a unique role for Sdc1 in this adipocyte sub-type. The PPARγ agonist rosiglitazone rescues Sdc1-/- intradermal adipose tissue, placing PPARγ downstream of Sdc1 in triggering adipocyte differentiation. Our study indicates that disruption of intradermal adipose tissue development results in cold stress and complex metabolic pathology.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Kasza
authors.affiliation: Department of Dermatology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Yewseok
authors.initials: Y
authors.lastname: Suh
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Damian
authors.initials: D
authors.lastname: Wollny
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Rod J
authors.initials: RJ
authors.lastname: Clark
authors.affiliation: Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Avtar
authors.initials: A
authors.lastname: Roopra
authors.affiliation: Wisconsin National Primate Research Center, Madison, Wisconsin, United States of America.
authors.forename: Ricki J
authors.initials: RJ
authors.lastname: Colman
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Ormond A
authors.initials: OA
authors.lastname: MacDougald
authors.affiliation: Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Shedd
authors.affiliation: Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Nelson
authors.affiliation: Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Mei-I
authors.initials: MI
authors.lastname: Yen
authors.affiliation: Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Chi-Liang Eric
authors.initials: CL
authors.lastname: Yen
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Alexander
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D003080:Cold Temperature; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000077154:Rosiglitazone; D013312:Stress, Physiological / Q000235:genetics*; D053668:Syndecan-1 / Q000235:genetics* / Q000378:metabolism; D045162:Thiazolidinediones / Q000008:administration & dosage
chemical_list: D047495:PPAR gamma; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D048308:Mitogen-Activated Protein Kinase 14
references.citation: J Lipid Res. 2004 Sep;45(9):1674-82
references.pmid: 15210843
references.citation: Cell Metab. 2009 Feb;9(2):203-9
references.pmid: 19187776
references.citation: Semin Cell Dev Biol. 2001 Apr;12(2):107-16
references.pmid: 11292376
references.citation: J Biol Chem. 2010 Jan 1;285(1):286-94
references.pmid: 19889634
references.citation: Nat Methods. 2011 Dec 28;9(1):57-63
references.pmid: 22205519
references.citation: Sci Signal. 2009 Dec 01;2(99):ra78
references.pmid: 19952371
references.citation: Nat Rev Cancer. 2007 Nov;7(11):834-46
references.pmid: 17957189
references.citation: Comp Biochem Physiol A Mol Integr Physiol. 2012 Apr;161(4):395-400
references.pmid: 22233932
references.citation: J Clin Invest. 2009 Nov;119(11):3236-45
references.pmid: 19805913
references.citation: J Exp Med. 2012 Jun 4;209(6):1069-74
references.pmid: 22665703
references.citation: J Clin Invest. 2007 Jan;117(1):153-64
references.pmid: 17200715
references.citation: J Clin Invest. 2000 Oct;106(7):847-56
references.pmid: 11018072
references.citation: J Biol Chem. 1999 Apr 30;274(18):12229-35
references.pmid: 10212189
references.citation: Oncogene. 2007 Mar 1;26(10):1407-16
references.pmid: 16953225
references.citation: Annu Rev Biochem. 1999;68:729-77
references.pmid: 10872465
references.citation: Am J Clin Nutr. 2010 Jan;91(1):254S-257S
references.pmid: 19906798
references.citation: Cell Metab. 2006 Oct;4(4):263-73
references.pmid: 17011499
references.citation: Diabetes. 2011 Jan;60(1):17-23
references.pmid: 21193735
references.citation: Proc Natl Acad Sci U S A. 1992 May 15;89(10):4471-5
references.pmid: 1584779
references.citation: Anal Biochem. 1974 Aug;60(2):405-12
references.pmid: 4844560
references.citation: Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12480-5
references.pmid: 23818608
references.citation: Genes Dev. 2013 Feb 15;27(4):355-71
references.pmid: 23431053
references.citation: Am J Physiol Gastrointest Liver Physiol. 2005 Jun;288(6):G1179-89
references.pmid: 15591160
references.citation: Prog Lipid Res. 2013 Jan;52(1):51-61
references.pmid: 22960032
references.citation: J Mol Med (Berl). 2012 Aug;90(8):887-93
references.pmid: 22231746
references.citation: Mol Endocrinol. 2004 Feb;18(2):384-401
references.pmid: 14630998
references.citation: Int J Obes (Lond). 2006 Jan;30(1):50-9
references.pmid: 16231032
references.citation: Nat Rev Mol Cell Biol. 2011 Sep 28;12(11):722-34
references.pmid: 21952300
references.citation: J Biol Chem. 1997 Dec 12;272(50):31738-46
references.pmid: 9395518
references.citation: J Lipid Res. 2013 Jun;54(6):1644-1652
references.pmid: 23536640
references.citation: Cell. 1999 Jul 9;98(1):115-24
references.pmid: 10412986
references.citation: Mol Cell Biol. 2004 Apr;24(7):3057-67
references.pmid: 15024092
references.citation: Curr Opin Neurobiol. 2003 Aug;13(4):487-92
references.pmid: 12965298
references.citation: Anat Rec. 1984 Dec;210(4):569-73
references.pmid: 6524697
references.citation: Physiol Behav. 2004 Jul;81(5):749-54
references.pmid: 15234180
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19378-83
references.pmid: 19033454
references.citation: Am J Physiol Endocrinol Metab. 2006 Aug;291(2):E350-7
references.pmid: 16595854
references.citation: Annu Rev Cell Dev Biol. 2006;22:339-73
references.pmid: 16824012
references.citation: J Mol Endocrinol. 2013 Nov 26;51(3):T75-85
references.pmid: 24041933
references.citation: Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1244-53
references.pmid: 20354155
references.citation: Nat Genet. 2000 Jul;25(3):329-32
references.pmid: 10888884
references.citation: Annu Rev Physiol. 2004;66:239-74
references.pmid: 14977403
references.citation: Mol Cell Biol. 2005 Jul;25(13):5466-79
references.pmid: 15964803
references.citation: Am J Pathol. 2009 Feb;174(2):519-33
references.pmid: 19147827
references.citation: J Clin Invest. 2012 Mar;122(3):1022-36
references.pmid: 22307324
references.citation: Nature. 2011 Nov 20;480(7375):104-8
references.pmid: 22101429
references.citation: Dermatoendocrinol. 2011 Apr;3(2):62-4
references.pmid: 21695013
references.citation: Front Physiol. 2013 Mar 14;4:34
references.pmid: 23504620
references.citation: Physiol Rev. 2004 Jan;84(1):277-359
references.pmid: 14715917
references.citation: J Cell Biol. 2004 Oct 11;167(1):171-81
references.pmid: 15479743
references.citation: Biol Bull. 1950 Oct;99(2):259-71
references.pmid: 14791423
references.citation: J Biol Chem. 2003 Aug 15;278(33):30413-6
references.pmid: 12788931
references.citation: Annu Rev Biochem. 2008;77:289-312
references.pmid: 18518822
references.citation: Matrix Biol. 2012 Jan;31(1):3-16
references.pmid: 22033227
references.citation: FASEB J. 2005 Jul;19(9):1205-7
references.pmid: 15857881
references.citation: Physiol Behav. 2013 Feb 17;110-111:87-95
references.pmid: 23313562
references.citation: Circulation. 2007 Jan 30;115(4):518-33
references.pmid: 17261671
references.citation: Prog Lipid Res. 2010 Apr;49(2):186-99
references.pmid: 20018209
references.citation: Nat Genet. 2004 Apr;36(4):343-50
references.pmid: 14991053
references.citation: Biochem Pharmacol. 2008 Oct 1;76(7):817-24
references.pmid: 18644349
references.citation: Nat Med. 2011 Feb;17(2):200-5
references.pmid: 21258337
references.citation: J Clin Invest. 2012 Jul;122(7):2405-16
references.pmid: 22728933
references.citation: Cell. 2011 Sep 2;146(5):761-71
references.pmid: 21884937
references.citation: J Invest Dermatol. 2010 Nov;130(11):2664-6
references.pmid: 20574444
references.citation: Diabetes. 2010 Feb;59(2):323-9
references.pmid: 20103710
references.citation: Nat Rev Cancer. 2009 Aug;9(8):537-49
references.pmid: 19629069
references.citation: Biochim Biophys Acta. 2014 Mar;1842(3):370-6
references.pmid: 23644163
references.citation: J Clin Invest. 2011 Jan;121(1):96-105
references.pmid: 21123942
references.citation: Nat Commun. 2013;4:1769
references.pmid: 23612310
references.citation: J Exp Biol. 2011 Jan 15;214(Pt 2):242-53
references.pmid: 21177944
references.citation: Front Endocrinol (Lausanne). 2011 Oct 31;2:64
references.pmid: 22654820
references.citation: Annu Rev Cell Dev Biol. 2010;26:89-114
references.pmid: 20565253
references.citation: Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E444-52
references.pmid: 17473055
references.citation: Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20176-81
references.pmid: 24248371
references.citation: J Clin Invest. 2005 Jun;115(6):1627-35
references.pmid: 15902306
references.citation: Biochemistry. 2006 May 9;45(18):5703-11
references.pmid: 16669614
references.citation: Lipids Health Dis. 2006 Aug 31;5:23
references.pmid: 16945147
references.citation: Cell Metab. 2010 Apr 7;11(4):257-62
references.pmid: 20374957
references.citation: Obes Res. 2000 Aug;8(5):392-8
references.pmid: 10968731
references.citation: Q J Exp Physiol Cogn Med Sci. 1959 Jan;44(1):35-42
references.pmid: 13624011
references.citation: Int J Biol Sci. 2009;5(1):44-51
references.pmid: 19159010
references.citation: Comp Biochem Physiol B Biochem Mol Biol. 2010 Nov;157(3):301-9
references.pmid: 20659581
references.citation: Adipocyte. 2013 Apr 1;2(2):104-8
references.pmid: 23805407