Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner.

Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE

Publication: New York Ny : Nature Publishing Company
Original Publication: New York, NY : Nature Pub. Co., [1995-

Forkhead Transcription Factors/*metabolism ; Glucose/*metabolism ; Insulin Resistance/*physiology ; Liver/*metabolism ; Receptor, Notch1/*metabolism ; Signal Transduction/*physiology; Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Animals ; Blotting, Western ; Chromatin Immunoprecipitation ; Forkhead Box Protein O1 ; Forkhead Transcription Factors/genetics ; Haploinsufficiency/genetics ; Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics ; Luciferases ; Mice ; Mice, Knockout ; Receptor, Notch1/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects

Transcription factor FoxO1 promotes hepatic glucose production. Genetic inhibition of FoxO1 function prevents diabetes in experimental animal models, providing impetus to identify pharmacological approaches to modulate this function. Altered Notch signaling is evident in tumorigenesis, and Notch antagonists are in clinical testing for application in cancer. Here we report that FoxO1 and Notch coordinately regulate hepatic glucose metabolism. Combined haploinsufficiency of FoxO1 and Notch1 markedly raises insulin sensitivity in diet-induced insulin resistance, as does liver-specific knockout of the Notch transcriptional effector Rbp-Jκ. Conversely, Notch1 gain-of-function promotes insulin resistance in a FoxO1-dependent manner and induces glucose-6-phosphatase expression. Pharmacological blockade of Notch signaling with γ-secretase inhibitors raises insulin sensitivity after in vivo administration in lean mice and in obese, insulin-resistant mice. The data identify a heretofore unknown metabolic function of Notch and suggest that Notch inhibition is beneficial in diabetes treatment, in part by helping to offset excessive FoxO1-driven hepatic glucose production.

Comment in: J Hepatol. 2012 Nov;57(5):1141-3. doi: 10.1016/j.jhep.2012.06.007. (PMID: 22705989)
Erratum in: Nat Med. 2024 Feb;30(2):604. doi: 10.1038/s41591-023-02695-9. (PMID: 38041001)

J Clin Invest. 2007 Sep;117(9):2477-85. (PMID: 17717603)
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2975-80. (PMID: 14978268)
Nature. 2009 Nov 12;462(7270):182-8. (PMID: 19907488)
J Biol Chem. 2003 Mar 14;278(11):9073-85. (PMID: 12496257)
Biochem Biophys Res Commun. 2009 Dec 25;390(4):1093-7. (PMID: 19853579)
Dev Cell. 2003 Jan;4(1):119-29. (PMID: 12530968)
Nat Med. 2009 Oct;15(10):1195-201. (PMID: 19767734)
Diabetes. 2010 Feb;59(2):337-46. (PMID: 19933998)
Diabetes. 2004 Jul;53(7):1633-42. (PMID: 15220184)
Cell Metab. 2006 Jan;3(1):59-65. (PMID: 16399505)
Diabetes. 2008 Mar;57(3):563-76. (PMID: 18162510)
Diabetes. 2009 Jun;58(6):1275-82. (PMID: 19289458)
Science. 2011 Mar 25;331(6024):1529-31. (PMID: 21436429)
Diabetes Obes Metab. 2001 Oct;3(5):367-80. (PMID: 11703427)
Hepatology. 2007 Feb;45(2):323-30. (PMID: 17366661)
J Biol Chem. 2000 Nov 17;275(46):36324-33. (PMID: 10960473)
Cell. 2007 Jan 26;128(2):309-23. (PMID: 17254969)
Cell Metab. 2005 Sep;2(3):153-63. (PMID: 16154098)
N Engl J Med. 2006 Dec 7;355(23):2427-43. (PMID: 17145742)
Curr Pharm Biotechnol. 2009 Feb;10(2):154-60. (PMID: 19199947)
Development. 2009 May;136(10):1727-39. (PMID: 19369401)
Semin Cell Dev Biol. 2009 Apr;20(2):219-24. (PMID: 19162210)
Cell. 2004 May 14;117(4):421-6. (PMID: 15137936)
Science. 2008 Nov 28;322(5906):1395-9. (PMID: 19039140)
Diabetes. 2006 Jul;55(7):2042-50. (PMID: 16804074)
J Clin Invest. 2001 Nov;108(9):1359-67. (PMID: 11696581)
Cell Metab. 2007 Sep;6(3):208-16. (PMID: 17767907)
Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E718-28. (PMID: 12783775)
Genesis. 2000 Feb;26(2):149-50. (PMID: 10686614)
Development. 2006 Sep;133(17):3277-82. (PMID: 16908627)
Mol Cell Biol. 2000 Mar;20(5):1825-35. (PMID: 10669757)
Development. 1995 Oct;121(10):3291-301. (PMID: 7588063)
J Biol Chem. 1999 Jun 4;274(23):15982-5. (PMID: 10347145)
Hum Mol Genet. 1999 May;8(5):723-30. (PMID: 10196361)
Nat Genet. 2002 Oct;32(2):245-53. (PMID: 12219087)
J Clin Invest. 2002 May;109(9):1125-31. (PMID: 11994399)
Oncogene. 2008 Sep 1;27(38):5132-7. (PMID: 18758482)
Toxicol Sci. 2004 Nov;82(1):341-58. (PMID: 15319485)
J Biol Chem. 2004 Jul 16;279(29):30771-80. (PMID: 15123653)
Dev Cell. 2009 May;16(5):633-47. (PMID: 19460341)
Nat Med. 2001 Aug;7(8):947-53. (PMID: 11479628)
Genes Dev. 2000 Jun 1;14(11):1343-52. (PMID: 10837027)
FEBS Lett. 2004 Jan 30;558(1-3):69-73. (PMID: 14759518)
J Biol Chem. 2010 Nov 12;285(46):35245-8. (PMID: 20880840)
J Biol Chem. 2007 Oct 12;282(41):30143-9. (PMID: 17724029)
Nature. 2005 Jun 16;435(7044):959-63. (PMID: 15959515)

DK63608 United States DK NIDDK NIH HHS; U24 DK076169 United States DK NIDDK NIH HHS; F32 DK084583 United States DK NIDDK NIH HHS; HL062454 United States HL NHLBI NIH HHS; DK084583 United States DK NIDDK NIH HHS; U24 DK059635 United States DK NIDDK NIH HHS; R01 HL062454 United States HL NHLBI NIH HHS; R24 DK085638 United States DK NIDDK NIH HHS; R37 DK058282 United States DK NIDDK NIH HHS; P30 DK045735 United States DK NIDDK NIH HHS; R01 DK057539 United States DK NIDDK NIH HHS; DK76169 United States DK NIDDK NIH HHS; P30 DK063608 United States DK NIDDK NIH HHS; United States HHMI Howard Hughes Medical Institute; DK57539 United States DK NIDDK NIH HHS; R01 DK040936 United States DK NIDDK NIH HHS

0 (Forkhead Box Protein O1)
0 (Forkhead Transcription Factors)
0 (Foxo1 protein, mouse)
0 (Immunoglobulin J Recombination Signal Sequence-Binding Protein)
0 (Notch1 protein, mouse)
0 (Receptor, Notch1)
EC 1.13.12.- (Luciferases)
EC 3.4.- (Amyloid Precursor Protein Secretases)
IY9XDZ35W2 (Glucose)

Date Created: 20110802 Date Completed: 20111017 Latest Revision: 20240610

20240610

PMC3387563

10.1038/nm.2378

21804540