Bone morphogenetic protein 2 is a depot-specific regulator of human adipogenesis.
Adipocytes
/ cytology
Adipogenesis
/ physiology
Adipose Tissue
/ cytology
Adult
Aged
Body Mass Index
Bone Morphogenetic Protein 2
/ metabolism
Cell Proliferation
/ physiology
Cells, Cultured
Female
Humans
Male
Middle Aged
Signal Transduction
/ physiology
Smad Proteins, Receptor-Regulated
/ metabolism
Journal
International journal of obesity (2005)
ISSN: 1476-5497
Titre abrégé: Int J Obes (Lond)
Pays: England
ID NLM: 101256108
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
07
02
2019
accepted:
17
05
2019
revised:
13
05
2019
pubmed:
22
7
2019
medline:
14
7
2020
entrez:
21
7
2019
Statut:
ppublish
Résumé
Bone morphogenetic proteins (BMPs) regulate adipogenesis but it is not clear whether they influence regional adipose tissue (AT) development in humans. To characterise BMP2 expression, BMP2-SMAD1/5/8 signalling, and BMP2's potential effect on proliferation and adipogenesis in human subcutaneous abdominal and gluteal AT and its constituent preadipocytes. BMP2 expression was measured in whole AT and immortalised preadipocytes via qPCR and Western blot; secreted/circulating BMP2 was measured by ELISA. The effect of BMP2 on preadipocyte proliferation was evaluated using a fluorescent assay. BMP2's effect on adipogenesis in immortalised preadipocytes was determined via qPCR of adipogenic markers and cellular triacylglycerol (TAG) accumulation. BMP2-SMAD1/5/8 signalling was assessed in immortalised preadipocytes via Western blot and qPCR of ID1 expression. BMP2 was expressed and released by abdominal and gluteal AT and preadipocytes. Exogenous BMP2 dose dependently promoted adipogenesis in abdominal preadipocytes only; 50 ng/ml BMP2 increased PPARG2 expression (10-fold compared to vehicle, p < 0.001) and TAG accumulation (3-fold compared to vehicle; p < 0.001). BMP2 stimulated SMAD1/5/8 phosphorylation and ID1 expression in abdominal and gluteal preadipocytes but this was blocked by 500 nM K02288, a type 1 BMP receptor inhibitor (p < 0.001). Co-administration of 500 nM K02288 also inhibited the pro-adipogenic effect of 50 ng/ml BMP2 in abdominal cells; >90% inhibition of TAG accumulation (p < 0.001) and ~50% inhibition of PPARG2 expression (p < 0.001). The endogenous iron regulator erythroferrone reduced BMP2-SMAD1/5/8 signalling by ~30% specifically in subcutaneous abdominal preadipocytes (p < 0.01), suggesting it plays a role in restricting the expansion of the body's largest AT depot during energy deficiency. Additionally, a waist-hip ratio-increasing common polymorphism near BMP2 is an eQTL associated with ~15% lower BMP2 expression in abdominal and gluteal AT (p < 0.05) as well as altered adipocyte size in male abdominal AT (p < 0.05). These data implicate BMP2-SMAD1/5/8 signalling in depot-specific preadipocyte development and abdominal AT expansion in humans.
Sections du résumé
BACKGROUND
Bone morphogenetic proteins (BMPs) regulate adipogenesis but it is not clear whether they influence regional adipose tissue (AT) development in humans.
OBJECTIVE
To characterise BMP2 expression, BMP2-SMAD1/5/8 signalling, and BMP2's potential effect on proliferation and adipogenesis in human subcutaneous abdominal and gluteal AT and its constituent preadipocytes.
METHODS
BMP2 expression was measured in whole AT and immortalised preadipocytes via qPCR and Western blot; secreted/circulating BMP2 was measured by ELISA. The effect of BMP2 on preadipocyte proliferation was evaluated using a fluorescent assay. BMP2's effect on adipogenesis in immortalised preadipocytes was determined via qPCR of adipogenic markers and cellular triacylglycerol (TAG) accumulation. BMP2-SMAD1/5/8 signalling was assessed in immortalised preadipocytes via Western blot and qPCR of ID1 expression.
RESULTS
BMP2 was expressed and released by abdominal and gluteal AT and preadipocytes. Exogenous BMP2 dose dependently promoted adipogenesis in abdominal preadipocytes only; 50 ng/ml BMP2 increased PPARG2 expression (10-fold compared to vehicle, p < 0.001) and TAG accumulation (3-fold compared to vehicle; p < 0.001). BMP2 stimulated SMAD1/5/8 phosphorylation and ID1 expression in abdominal and gluteal preadipocytes but this was blocked by 500 nM K02288, a type 1 BMP receptor inhibitor (p < 0.001). Co-administration of 500 nM K02288 also inhibited the pro-adipogenic effect of 50 ng/ml BMP2 in abdominal cells; >90% inhibition of TAG accumulation (p < 0.001) and ~50% inhibition of PPARG2 expression (p < 0.001). The endogenous iron regulator erythroferrone reduced BMP2-SMAD1/5/8 signalling by ~30% specifically in subcutaneous abdominal preadipocytes (p < 0.01), suggesting it plays a role in restricting the expansion of the body's largest AT depot during energy deficiency. Additionally, a waist-hip ratio-increasing common polymorphism near BMP2 is an eQTL associated with ~15% lower BMP2 expression in abdominal and gluteal AT (p < 0.05) as well as altered adipocyte size in male abdominal AT (p < 0.05).
CONCLUSIONS
These data implicate BMP2-SMAD1/5/8 signalling in depot-specific preadipocyte development and abdominal AT expansion in humans.
Identifiants
pubmed: 31324879
doi: 10.1038/s41366-019-0421-1
pii: 10.1038/s41366-019-0421-1
pmc: PMC6892741
mid: EMS83222
doi:
Substances chimiques
BMP2 protein, human
0
Bone Morphogenetic Protein 2
0
Smad Proteins, Receptor-Regulated
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2458-2468Subventions
Organisme : Medical Research Council
ID : MC_UU_00008/10
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12010/10
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/17/1/32663
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Références
Science. 1988 Dec 16;242(4885):1528-34
pubmed: 3201241
Diabetologia. 2012 Nov;55(11):3029-37
pubmed: 22898765
Am J Physiol Cell Physiol. 2014 Mar 1;306(5):C431-40
pubmed: 24284793
Obesity (Silver Spring). 2016 Oct;24(10):2092-100
pubmed: 27515773
Diabetologia. 2018 Feb;61(2):369-380
pubmed: 29067487
Dev Cell. 2006 Apr;10(4):461-71
pubmed: 16580992
Nucleic Acids Res. 2011 Nov 1;39(20):8712-27
pubmed: 21764776
Adipocyte. 2017 Jan 2;6(1):40-55
pubmed: 28452592
Nature. 2015 Feb 12;518(7538):187-196
pubmed: 25673412
Mol Biol Cell. 2003 Feb;14(2):545-55
pubmed: 12589053
Int J Mol Sci. 2016 Jan 20;17(1):
pubmed: 26805813
Diabetes. 2014 Nov;63(11):3785-97
pubmed: 24947352
Clin Sci (Lond). 1989 May;76(5):509-16
pubmed: 2721118
FEBS Lett. 2000 Jun 23;475(3):201-4
pubmed: 10869556
Obesity (Silver Spring). 2011 Apr;19(4):888-92
pubmed: 20948521
Genes Dev. 1998 Jan 15;12(2):186-97
pubmed: 9436979
J Cell Biol. 1998 Jul 13;142(1):295-305
pubmed: 9660882
J Biol Chem. 2002 Feb 1;277(5):3176-85
pubmed: 11700304
Obesity (Silver Spring). 2016 Feb;24(2):398-407
pubmed: 26813528
J Cell Biochem. 2015 Oct;116(10):2127-38
pubmed: 25776852
Obesity (Silver Spring). 2010 May;18(5):1055-8
pubmed: 20057374
Diabetes. 2015 May;64(5):1670-81
pubmed: 25605802
Diabetes Care. 2014;37(3):821-9
pubmed: 24186879
PLoS One. 2013 Apr 30;8(4):e62721
pubmed: 23646137
Tissue Eng Part A. 2016 Feb;22(3-4):214-21
pubmed: 26585335
Diabetes. 2012 May;61(5):1217-24
pubmed: 22447857
Int J Epidemiol. 2018 Feb 1;47(1):21-21g
pubmed: 29040543
J Clin Endocrinol Metab. 2013 Jan;98(1):362-71
pubmed: 23150689
Proc Natl Acad Sci U S A. 1990 Mar;87(6):2220-4
pubmed: 2315314
Front Biosci (Landmark Ed). 2014 Jun 01;19(8):1386-97
pubmed: 24896358
Nature. 2010 Mar 25;464(7288):619-23
pubmed: 20200519
Blood. 2017 Jul 6;130(1):73-83
pubmed: 28438754
Cytokine Growth Factor Rev. 2009 Oct-Dec;20(5-6):475-80
pubmed: 19892583
Calcif Tissue Int. 1998 Sep;63(3):221-9
pubmed: 9701626
Cytokine. 2013 Oct;64(1):138-45
pubmed: 23911203
Nucleic Acids Res. 2001 May 1;29(9):e45
pubmed: 11328886
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12670-5
pubmed: 19620713
J Biol Chem. 2006 Aug 11;281(32):23246-53
pubmed: 16754660
Crit Rev Clin Lab Sci. 2015;52(6):301-13
pubmed: 26292076
Nature. 2010 Oct 14;467(7317):832-8
pubmed: 20881960
Nat Rev Endocrinol. 2015 Feb;11(2):90-100
pubmed: 25365922
Exp Eye Res. 2008 Aug;87(2):78-9
pubmed: 18201700
Tissue Eng Part A. 2014 Nov;20(21-22):3031-40
pubmed: 24854876
Diabetol Metab Syndr. 2012 Sep 19;4(1):42
pubmed: 22992414
Cardiovasc Diabetol. 2015 May 24;14:64
pubmed: 26003174
Diabetes. 2012 Jul;61(7):1691-9
pubmed: 22596050
J Biol Chem. 2010 Feb 26;285(9):6044-52
pubmed: 20032470