title: Characterization of the role of sphingomyelin synthase 2 in glucose metabolism in whole-body and peripheral tissues in mice.
abstract: Sphingomyelin synthase 2 (SMS2) is a proposed potential therapeutic target for obesity and insulin resistance. However, the contributions of SMS2 to glucose metabolism in tissues and its possible therapeutic mechanisms remain unclear. Thus, to determine whole-body glucose utilization and the contributions of each insulin-targeted tissue to glucose uptake, we performed a glucose kinetics study, using the radiolabeled glucose analog (18)F-2-fluoro-2-deoxy-D-glucose ((18)F-FDG), in wild-type (WT) and SMS2 knockout (KO) mice. Insulin signaling was enhanced in the liver, white adipose tissue and skeletal muscle of SMS2 KO mice compared with those of WT mice. In addition, compared with in WT mice, blood clearance of (18)F-FDG was accelerated in SMS2 KO mice when they were fed either a normal or a high fat diet. (18)F-FDG uptake was also increased in insulin-targeted tissues such as skeletal muscle in the SMS2 KO mice. Whereas skeletal muscle sphingolipid content was not clearly affected, plasma levels of very long-chain fatty acid (VLCFA)-containing ceramides were markedly increased in SMS2 KO mice, compared with in WT mice. We also generated liver-conditional SMS2 KO mice and performed glucose and insulin tolerance tests on mice with a high fat diet. However, no significant effect was observed. Thus, our study provided evidence that genetic inhibition of SMS2 elevated glucose clearance through activation of glucose uptake into insulin-targeted tissues such as skeletal muscle by a mechanism independent of hepatic SMS2. Our findings further indicate that this occurs, at least in part, via indirect mechanisms such as elevation of VLCFA-containing ceramides.
authors.affiliation: Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Sapporo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sugimoto
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan; Laboratory of Bioanalysis and Molecular Imaging, Faculty of Pharmaceutical Science, Hokkaido University, Sapporo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Department of Tracer Kinetics & Bioanalysis, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Songji
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Tracer Kinetics & Bioanalysis, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Ukon
authors.affiliation: Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Nishijima
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Sapporo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Wakabayashi
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Sapporo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshioka
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Sapporo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Higashino
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Sapporo, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Numata
authors.affiliation: Drug Discovery Technologies, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Okuda
authors.affiliation: Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Nagara
authors.initials: N
authors.lastname: Tamaki
authors.affiliation: Department of Biomembrane and Biofunctional Chemistry, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan.
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Hanamatsu
authors.affiliation: Department of Biomembrane and Biofunctional Chemistry, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
authors.affiliation: Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan. Electronic address: kuge@ric.hokudai.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
mesh_terms: D052436:Adipose Tissue, White / Q000201:enzymology*; D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology*; D009928:Organ Specificity; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D017855:Transferases (Other Substituted Phosphate Groups); C543123:Sgms2 protein, mouse; D005947:Glucose
keywords: (18)F-2-fluoro-2-deoxy-d-glucose; Ceramide; Glucose uptake; Insulin resistance; Sphingomyelin; Very long-chain fatty acid