title: Involvement of heparan sulfate 6-O-sulfation in the regulation of energy metabolism and the alteration of thyroid hormone levels in male mice.
abstract: Here, we report that male heparan sulfate 6-O-sulfotransferase-2 (Hs6st2) knockout mice showed increased body weight in an age-dependent manner even when fed with a normal diet and showed a phenotype of impaired glucose metabolism and insulin resistance. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that the expression of mitochondrial uncoupling proteins Ucp1 and Ucp3 was reduced in the interscapular brown adipose tissue (BAT) of male Hs6st2 knockout mice, suggesting reduced energy metabolism. The serum level of thyroid-stimulating hormone was significantly higher and that of thyroxine was lower in the knockout mice. When cultures of brown adipocytes from wild-type and Hs6st2 knockout mice isolated and differentiated in vitro were treated with FGF19 (fibroblast growth factor 19) or FGF21 in the presence or the absence of heparitinase I, phosphorylation of p42/p44 mitogen-activated protein (MAP) kinase was reduced. Heparan sulfate (HS) 6-O-sulfation was reduced not only in BAT but also in the thyroid tissue of the knockout mice. Thus, 6-O-sulfation in HS seems to play an important role in mediating energy metabolism by controlling thyroid hormone levels and signals from the FGF19 subfamily proteins, and the alteration of the HS composition may result in metabolic syndrome phenotypes such as altered glucose and insulin tolerance.
authors.affiliation: Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Nagai
authors.forename: Hiroko
authors.initials: H
authors.lastname: Habuchi
authors.forename: Noriko
authors.initials: N
authors.lastname: Sugaya
authors.forename: Masao
authors.initials: M
authors.lastname: Nakamura
authors.forename: Toru
authors.initials: T
authors.lastname: Imamura
authors.forename: Hideto
authors.initials: H
authors.lastname: Watanabe
authors.forename: Koji
authors.initials: K
authors.lastname: Kimata
mesh_terms: D052437:Adipocytes, Brown / Q000187:drug effects / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000473:pathology; D000367:Age Factors; D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism; D013963:Thyroid Hormones / Q000097:blood*; D013974:Thyroxine / Q000097:blood; D014158:Transcription, Genetic; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; D015430:Weight Gain
chemical_list: D005346:Fibroblast Growth Factors; D005947:Glucose; D006497:Heparan Sulfate; D007473:Ion Channels; D024101:Mitochondrial Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015238:Sulfotransferases; D013963:Thyroid Hormones; D013974:Thyroxine; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; C000604372:Ucp1 protein, mouse; C000604393:Ucp3 protein, mouse; C485758:Hs6st2 protein, mouse
keywords: FGF19; FGF21; heparan sulfate; thermogenesis; thyroid hormone