title: Reducing plasma membrane sphingomyelin increases insulin sensitivity.
abstract: It has been shown that inhibition of de novo sphingolipid synthesis increases insulin sensitivity. For further exploration of the mechanism involved, we utilized two models: heterozygous serine palmitoyltransferase (SPT) subunit 2 (Sptlc2) gene knockout mice and sphingomyelin synthase 2 (Sms2) gene knockout mice. SPT is the key enzyme in sphingolipid biosynthesis, and Sptlc2 is one of its subunits. Homozygous Sptlc2-deficient mice are embryonic lethal. However, heterozygous Sptlc2-deficient mice that were viable and without major developmental defects demonstrated decreased ceramide and sphingomyelin levels in the cell plasma membranes, as well as heightened sensitivity to insulin. Moreover, these mutant mice were protected from high-fat diet-induced obesity and insulin resistance. SMS is the last enzyme for sphingomyelin biosynthesis, and SMS2 is one of its isoforms. Sms2 deficiency increased cell membrane ceramide but decreased SM levels. Sms2 deficiency also increased insulin sensitivity and ameliorated high-fat diet-induced obesity. We have concluded that Sptlc2 heterozygous deficiency- or Sms2 deficiency-mediated reduction of SM in the plasma membranes leads to an improvement in tissue and whole-body insulin sensitivity.
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Ave. Box 5, Brooklyn, NY 11203, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Li
authors.forename: Hongqi
authors.initials: H
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Liang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.forename: Gladys
authors.initials: G
authors.lastname: Teitelman
authors.forename: Thomas
authors.initials: T
authors.lastname: Beyer
authors.forename: Hai H
authors.initials: HH
authors.lastname: Bui
authors.forename: David A
authors.initials: DA
authors.lastname: Peake
authors.forename: Youyan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Sanders
authors.forename: Ming-Shang
authors.initials: MS
authors.lastname: Kuo
authors.forename: Tae-Sik
authors.initials: TS
authors.lastname: Park
authors.forename: Guoqing
authors.initials: G
authors.lastname: Cao
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Jiang
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D006579:Heterozygote; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011972:Receptor, Insulin / Q000378:metabolism; D051102:Serine C-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D013109:Sphingomyelins / Q000032:analysis / Q000378:metabolism*; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D013109:Sphingomyelins; D051102:Serine C-Palmitoyltransferase; C495090:Sptlc2 protein, mouse; D011972:Receptor, Insulin; D017855:Transferases (Other Substituted Phosphate Groups); C543123:Sgms2 protein, mouse