title: NAADP mediates insulin-stimulated glucose uptake and insulin sensitization by PPARγ in adipocytes.
abstract: Insulin stimulates glucose uptake through the membrane translocation of GLUT4 and GLUT1. Peroxisome proliferator-activated receptor γ (PPARγ) enhances insulin sensitivity. Here, we demonstrate that insulin stimulates GLUT4 and GLUT1 translocation, and glucose uptake, by activating the signaling pathway involving nicotinic acid adenine dinucleotide phosphate (NAADP), a calcium mobilizer, in adipocytes. We also demonstrate that PPARγ mediates insulin sensitization by enhancing NAADP production through upregulation of CD38, the only enzyme identified for NAADP synthesis. Insulin produced NAADP by both CD38-dependent and -independent pathways, whereas PPARγ produced NAADP by CD38-dependent pathway. Blocking the NAADP signaling pathway abrogated both insulin-stimulated and PPARγ-induced GLUT4 and GLUT1 translocation, thereby inhibiting glucose uptake. CD38 knockout partially inhibited insulin-stimulated glucose uptake. However, CD38 knockout completely blocked PPARγ-induced glucose uptake in adipocytes and PPARγ-mediated amelioration of glucose tolerance in diabetic mice. These results demonstrated that the NAADP signaling pathway is a critical molecular target for PPARγ-mediated insulin sensitization.
authors.affiliation: Department of Microbiology, Chonbuk National University Medical School, Jeonju 561-756, Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Song
authors.forename: Young-Rae
authors.initials: YR
authors.lastname: Lee
authors.forename: Yu-Ri
authors.initials: YR
authors.lastname: Kim
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Yeom
authors.forename: Chae-Hwa
authors.initials: CH
authors.lastname: Yoo
authors.forename: Hyun-Kag
authors.initials: HK
authors.lastname: Kim
authors.forename: Hye-Min
authors.initials: HM
authors.lastname: Park
authors.forename: Hyung-Sub
authors.initials: HS
authors.lastname: Kang
authors.forename: Jong-Suk
authors.initials: JS
authors.lastname: Kim
authors.forename: Uh-Hyun
authors.initials: UH
authors.lastname: Kim
authors.forename: Myung-Kwan
authors.initials: MK
authors.lastname: Han
mesh_terms: D041721:3T3-L1 Cells; D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009249:NADP / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; D008562:Membrane Glycoproteins; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D009249:NADP; C024376:NAADP; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D005947:Glucose