Increased insulin sensitivity and reduced adiposity in phosphatidylinositol 5-phosphate 4-kinase β-/- mice

被引:92
作者
Lamia, KA
Peroni, OD
Kim, YB
Rameh, LE
Kahn, BB
Cantley, LC
机构
[1] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA
[3] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA USA
[4] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA
[5] Boston Biomed Res Inst, Watertown, MA USA
关键词
D O I
10.1128/MCB.24.11.5080-5087.2004
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Phosphorylated derivatives of the lipid phosphatidylinositoll are known to play critical roles in insulin response. Phosphatidylinositol 5-phosphate 4-kinases convert phosphatidlylinositol 5-phosphate to phosphatidylinositol 4,5-bis-phosphate. To understand the physiological role of these kinases, we generated mice that do not express phosphatidylinositol 5-phosphate 4-kinase beta. These mice are hypersensitive to insulin and have reduced body weights compared to wild-type littermates. While adult mate mice lacking phosphatidylinositol 5-phosphate 4-kinase beta have significantly less body fat than wild-type littermates, female mice lacking phosphatidylinositol 5-phosphate 4-kinase beta have increased insulin sensitivity in the presence of normal adiposity. Furthermore, in vivo insulin-induced activation of the protein kinase Akt is enhanced in skeletal muscle and liver from mice lacking phosphatidlylinositol 5-phosphate 4-kinase beta. These results indicate that phosphatidylinositol 5-phosphate 4-kinase beta plays a role in determining insulin sensitivity and adiposity in vivo and suggest that inhibitors of this enzyme may be useful in the treatment of type 2 diabetes.
引用
收藏
页码:5080 / 5087
页数:8
相关论文
共 36 条
[1]   Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver [J].
Abel, ED ;
Peroni, O ;
Kim, JK ;
Kim, YB ;
Boss, O ;
Hadro, E ;
Minnemann, T ;
Shulman, GI ;
Kahn, BB .
NATURE, 2001, 409 (6821) :729-733
[2]   Early neonatal death in mice homozygous for a null allele of the insulin receptor gene [J].
Accili, D ;
Drago, J ;
Lee, EJ ;
Johnson, MD ;
Cool, MH ;
Salvatore, P ;
Asico, LD ;
Jose, PA ;
Taylor, SI ;
Westphal, H .
NATURE GENETICS, 1996, 12 (01) :106-109
[3]   ALTERNATIVE PATHWAY OF INSULIN SIGNALING IN MICE WITH TARGETED DISRUPTION OF THE IRS-1 GENE [J].
ARAKI, E ;
LIPES, MA ;
PATTI, ME ;
BRUNING, JC ;
HAAG, B ;
JOHNSON, RS ;
KAHN, CR .
NATURE, 1994, 372 (6502) :186-190
[4]   Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance [J].
Blüher, M ;
Michael, MD ;
Peroni, OD ;
Ueki, K ;
Carter, N ;
Kahn, BB ;
Kahn, CR .
DEVELOPMENTAL CELL, 2002, 3 (01) :25-38
[5]   Role of brain insulin receptor in control of body weight and reproduction [J].
Brüning, JC ;
Gautam, D ;
Burks, DJ ;
Gillette, J ;
Schubert, M ;
Orban, PC ;
Klein, R ;
Krone, W ;
Müller-Wieland, D ;
Kahn, CR .
SCIENCE, 2000, 289 (5487) :2122-2125
[6]   Transcription - Translocating tubby [J].
Cantley, LC .
SCIENCE, 2001, 292 (5524) :2019-+
[7]   Abdominal fat and insulin resistance in normal and overweight women - Direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM [J].
Carey, DG ;
Jenkins, AB ;
Campbell, LV ;
Freund, J ;
Chisholm, DJ .
DIABETES, 1996, 45 (05) :633-638
[8]   The phosphatidylinositol (PI)-5-phosphate 4-kinase type II enzyme controls insulin signaling by regulating PI-3,4,5-trisphosphate degradation [J].
Carricaburu, V ;
Lamia, KA ;
Lo, E ;
Favereaux, L ;
Payrastre, B ;
Cantley, LC ;
Rameh, LE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (17) :9867-9872
[9]   A novel interaction between the juxtamembrane region of the p55 tumor necrosis factor receptor and phosphatidylinositol-4-phosphate 5-kinase [J].
Castellino, AM ;
Parker, GJ ;
Boronenkov, IV ;
Anderson, RA ;
Chao, MV .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (09) :5861-5870
[10]   Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ) [J].
Cho, H ;
Mu, J ;
Kim, JK ;
Thorvaldsen, JL ;
Chu, QW ;
Crenshaw, EB ;
Kaestner, KH ;
Bartolomei, MS ;
Shulman, GI ;
Birnbaum, MJ .
SCIENCE, 2001, 292 (5522) :1728-1731