The imprinted gene Delta like non-canonical notch ligand 1 (Dlk1) associates with obesity and triggers insulin resistance through inhibition of skeletal muscle glucose uptake.
Adipose Tissue
/ metabolism
Adiposity
Adult
Animals
Calcium-Binding Proteins
/ genetics
Cell Line
Disease Models, Animal
Female
Genomic Imprinting
Glucose
/ metabolism
Humans
Insulin Resistance
Male
Mice
Mice, Knockout
Middle Aged
Muscle, Skeletal
/ metabolism
Obesity
/ diagnostic imaging
Positron Emission Tomography Computed Tomography
Young Adult
Dlk1
Glucose uptake
Insulin resistance
Obesity
Type 2 diabetes
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Aug 2019
Aug 2019
Historique:
received:
14
03
2019
revised:
29
07
2019
accepted:
29
07
2019
pubmed:
7
8
2019
medline:
16
1
2020
entrez:
7
8
2019
Statut:
ppublish
Résumé
The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is considered an inhibitor of adipogenesis, but its in vivo impact on fat mass indeed remains elusive and controversial. Fat deposits were assessed by MRI and DXA scanning in two cohorts of non-diabetic men, whereas glucose disposal rate (GDR) was determined during euglycemic hyperinsulinemic clamp. Blood analyte measurements were used for correlation and mediation analysis to investigate how age, BMI, and fat percentage affect the relation between DLK1 and GDR. Confirmatory animal studies performed in normal (NC) and high fat diet (HFD) fed Dlk1 Overall, DLK1 is positively correlated with fat amounts, which is consistent with a negative linear relationship between DLK1 and GDR. This relationship is not mediated by age, BMI, or fat percentage. In support, DLK1 also correlates positively with HOMA-IR and ADIPO-IR in these humans, but has no linear relationship with the early diabetic inflammation marker MCP-1. In Dlk1 Thus, instead of an adipogenic inhibitor, Dlk1 should be regarded as a factor causally linked to obesity and insulin resistance, and may be used to predict development of type 2 diabetes. FUND: The Danish Diabetes Academy supported by the Novo Nordisk Foundation, The Danish National Research Council (#09-073648), The Lundbeck Foundation, University of Southern Denmark, and Dep. Of Clinical Biochemistry and Pharmacology/Odense University Hospital, the Swedish Research Council, the Swedish Diabetes Foundation, the Strategic Research Program in Diabetes at Karolinska Institute and an EFSD/Lilly grant.
Sections du résumé
BACKGROUND
BACKGROUND
The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is considered an inhibitor of adipogenesis, but its in vivo impact on fat mass indeed remains elusive and controversial.
METHODS
METHODS
Fat deposits were assessed by MRI and DXA scanning in two cohorts of non-diabetic men, whereas glucose disposal rate (GDR) was determined during euglycemic hyperinsulinemic clamp. Blood analyte measurements were used for correlation and mediation analysis to investigate how age, BMI, and fat percentage affect the relation between DLK1 and GDR. Confirmatory animal studies performed in normal (NC) and high fat diet (HFD) fed Dlk1
FINDINGS
RESULTS
Overall, DLK1 is positively correlated with fat amounts, which is consistent with a negative linear relationship between DLK1 and GDR. This relationship is not mediated by age, BMI, or fat percentage. In support, DLK1 also correlates positively with HOMA-IR and ADIPO-IR in these humans, but has no linear relationship with the early diabetic inflammation marker MCP-1. In Dlk1
INTERPRETATION
CONCLUSIONS
Thus, instead of an adipogenic inhibitor, Dlk1 should be regarded as a factor causally linked to obesity and insulin resistance, and may be used to predict development of type 2 diabetes. FUND: The Danish Diabetes Academy supported by the Novo Nordisk Foundation, The Danish National Research Council (#09-073648), The Lundbeck Foundation, University of Southern Denmark, and Dep. Of Clinical Biochemistry and Pharmacology/Odense University Hospital, the Swedish Research Council, the Swedish Diabetes Foundation, the Strategic Research Program in Diabetes at Karolinska Institute and an EFSD/Lilly grant.
Identifiants
pubmed: 31383551
pii: S2352-3964(19)30512-2
doi: 10.1016/j.ebiom.2019.07.070
pmc: PMC6711890
pii:
doi:
Substances chimiques
Calcium-Binding Proteins
0
Dlk1 protein, mouse
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
368-380Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
Références
Differentiation. 1999 Jan;64(2):103-14
pubmed: 10234807
Mol Cell Biol. 2002 Aug;22(15):5585-92
pubmed: 12101250
J Clin Invest. 2003 Feb;111(4):453-61
pubmed: 12588883
Diabetes Care. 2004 Jun;27(6):1487-95
pubmed: 15161807
J Biol Chem. 1992 Mar 25;267(9):6278-85
pubmed: 1556135
Diabetes. 2004 Dec;53 Suppl 3:S215-9
pubmed: 15561913
Exp Cell Res. 2005 Feb 15;303(2):343-59
pubmed: 15652348
J Mol Biol. 2007 Apr 13;367(5):1281-93
pubmed: 17320900
Endocrinology. 2007 Jul;148(7):3111-21
pubmed: 17446189
Diabetes. 2008 Feb;57(2):315-24
pubmed: 17977960
FEBS Lett. 2008 Jan 9;582(1):97-105
pubmed: 18053812
BMC Dev Biol. 2008 Jan 31;8:11
pubmed: 18237417
Clin Endocrinol (Oxf). 2008 Aug;69(2):216-24
pubmed: 18248640
Int J Obes (Lond). 2008 Jul;32(7):1122-9
pubmed: 18392037
Nature. 2008 Jun 5;453(7196):783-7
pubmed: 18454136
Stem Cells Dev. 2008 Jun;17(3):495-507
pubmed: 18513163
Am J Physiol Endocrinol Metab. 2008 Dec;295(6):E1323-32
pubmed: 18812462
Diabetes. 2008 Dec;57(12):3258-66
pubmed: 18835937
Mol Endocrinol. 2009 Nov;23(11):1717-25
pubmed: 19541743
Diabetes Care. 2009 Nov;32(11):2105-10
pubmed: 19641159
FEBS Lett. 2009 Sep 3;583(17):2947-53
pubmed: 19665021
Hepatology. 2009 Oct;50(4):1087-93
pubmed: 19670459
Mol Cell Biol. 2010 Jul;30(14):3480-92
pubmed: 20457810
Age (Dordr). 2012 Feb;34(1):145-56
pubmed: 21347608
Biochim Biophys Acta. 2011 Jun;1813(6):1153-64
pubmed: 21419176
Nature. 2011 Jul 20;475(7356):381-5
pubmed: 21776083
EJNMMI Res. 2011 Jul 6;1:8
pubmed: 21841971
Diabet Med. 2012 May;29(5):622-7
pubmed: 22023514
Eur J Endocrinol. 2012 Mar;166(3):469-76
pubmed: 22190001
Cell Metab. 2012 Feb 8;15(2):209-21
pubmed: 22326222
Diabetes. 2012 Aug;61(8):1986-93
pubmed: 22688341
J Atheroscler Thromb. 2012;19(10):941-8
pubmed: 22785051
Diabetes. 2012 Nov;61(11):2814-22
pubmed: 22891218
Mech Dev. 2013 Feb;130(2-3):143-59
pubmed: 23059197
Development. 2013 Sep;140(18):3743-53
pubmed: 23946446
Horm Metab Res. 2013 Oct;45(11):820-6
pubmed: 23979788
Mediators Inflamm. 2013;2013:539156
pubmed: 24089589
Mol Cancer Res. 2014 Jan;12(1):155-64
pubmed: 24249679
Nat Rev Genet. 2014 Aug;15(8):517-30
pubmed: 24958438
PLoS One. 2014 Jun 26;9(6):e99785
pubmed: 24968098
Physiol Rep. 2014 Jul 22;2(7):null
pubmed: 25052490
Cell Rep. 2014 Aug 7;8(3):678-87
pubmed: 25088414
Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):16088-93
pubmed: 25349437
Alcohol. 2014 Dec;48(8):795-800
pubmed: 25449367
Cytokine. 2015 Feb;71(2):161-4
pubmed: 25461394
Mediators Inflamm. 2014;2014:834294
pubmed: 25614714
Aging Clin Exp Res. 2015 Aug;27(4):403-11
pubmed: 25647784
Diabetes. 2015 Sep;64(9):3069-80
pubmed: 25918236
Physiol Rep. 2015 May 11;3(5):null
pubmed: 25969463
Diabet Med. 2016 May;33(5):631-8
pubmed: 26220259
Int J Obes (Lond). 2016 Feb;40(2):356-65
pubmed: 26315841
Stem Cell Res. 2015 Sep;15(2):403-18
pubmed: 26342195
Curr Pharm Des. 2016;22(7):895-903
pubmed: 26648466
Cell Signal. 2016 Apr;28(4):246-54
pubmed: 26791579
Bone. 2018 May;110:312-320
pubmed: 29499415
J Clin Invest. 2018 Apr 2;128(4):1538-1550
pubmed: 29528335
Jpn J Radiol. 2018 Sep;36(9):528-536
pubmed: 29948547
Cell. 1993 May 21;73(4):725-34
pubmed: 8500166
J Reprod Fertil. 1996 Jul;107(2):279-85
pubmed: 8882295
Clin Chim Acta. 1997 Dec 10;268(1-2):1-20
pubmed: 9495567
J Cell Biol. 1998 Sep 21;142(6):1429-46
pubmed: 9744875