Depot specific differences in the adipogenic potential of precursors are mediated by collagenous extracellular matrix and Flotillin 2 dependent signaling.
OBJECTIVE
Adipose tissue shows a high degree of plasticity, and adipocyte hyperplasia is an important mechanism for adipose tissue expansion. Different adipose depots respond differently to an increased demand for lipid storage. Orchestrating cellular expansion in vivo requires extracellular matrix (ECM) remodeling and a high degree of interaction between cells and ECM.


METHODS
We studied decellularized primary adipose stromal cell derived ECM of different adipose depots and reseeded them with primary adipose precursors. We tested ECM effect on adipocyte differentiation and analyzed ECM composition using proteomic and immunohistochemical approaches to identify factors in the ECM influencing adipogenesis.


RESULTS
We show that the ECM of an adipose depot is the major determinant for the differentiation capacity of primary preadipocytes. Visceral adipose tissue stromal cells differentiate less than subcutaneous cells, which, in turn, are less adipogenic than BAT-derived cells. This effect is based on the ECM composition of the respective depot and not dependent on the precursor origin. Addition of vitamin C pronounces the pro-adipogenic effects of the ECM, indicating the importance of collagenous ECM in mediating the effect. Using a proteomic global and a targeted downstream analysis, we identify Flotillin 2 as a protein enriched in pro-adipogenic ECM, which is involved in orchestrating ECM to preadipocyte signaling.


CONCLUSIONS
We show that adipose tissue SVF secretes collagenous ECM, which directly modulates terminal differentiation of adipocyte precursors in a depot specific manner. These data demonstrate the importance of the tissue microenvironment in preadipocyte differentiation.
Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
Gerald
G
Grandl
Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland; Institute of Molecular Systems Biology, ETH Zürich, Switzerland.
Sebastian
S
Müller
Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland; Institute of Molecular Systems Biology, ETH Zürich, Switzerland.
Hansjörg
H
Moest
Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
Caroline
C
Moser
Institute of Molecular Systems Biology, ETH Zürich, Switzerland.
Bernd
B
Wollscheid
Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland. Electronic address: christian-wolfrum@ethz.ch.
Christian
C
Wolfrum
Adipocyte precursors; Collagen; Extracellular matrix; Flotillin 2; Stem cell niche
Nat Med. 2013 Oct;19(10):1338-44
23995282
Cell. 2015 Oct 22;163(3):712-23
26496610
Nat Biotechnol. 2012 Oct;30(10):918-20
23051804
Differentiation. 2002 May;70(2-3):84-91
12076335
Cell Metab. 2014 Jul 1;20(1):103-18
24930973
Diabetes. 2012 Jul;61(7):1691-9
22596050
Cell Metab. 2014 Dec 2;20(6):1049-58
25456741
Science. 2008 Oct 24;322(5901):583-6
18801968
Cell. 1994 Dec 30;79(7):1147-56
8001151
Cancer Res. 2004 Oct 15;64(20):7361-9
15492257
Cell Metab. 2013 May 7;17(5):644-56
23583168
EMBO Mol Med. 2011 Nov;3(11):637-51
21853531
Lancet. 2016 Apr 2;387(10026):1377-96
27115820
Nat Mater. 2012 May 27;11(7):642-9
22635042
Stem Cells. 2009 Oct;27(10):2563-70
19658193
Biochim Biophys Acta. 2016 Sep;1861(9 Pt A):1121-31
27317982
Cell. 2006 May 5;125(3):577-91
16678100
Nat Methods. 2011 Jan;8(1):70-3
21131968
Cell. 2014 Jan 16;156(1-2):20-44
24439368
J Cell Sci. 2011 Dec 1;124(Pt 23):3933-40
22194304
Cell Metab. 2012 Apr 4;15(4):480-91
22482730
Nature. 2011 Jun 08;474(7350):179-83
21654799
J Biol Chem. 1997 May 23;272(21):13793-802
9153235
Development. 1997 Jan;124(2):577-87
9053333
Cell Metab. 2013 Sep 3;18(3):355-67
24011071
Cell. 2008 Oct 17;135(2):240-9
18835024
Nat Cell Biol. 2015 Apr;17(4):376-85
25730471
Proteomics. 2010 Mar;10(6):1150-9
20101611
Nat Protoc. 2013 Aug;8(8):1551-66
23868073
Curr Protoc Cell Biol. 2007 Jan;Chapter 10:Unit 10.9
18228495
Nat Rev Mol Cell Biol. 2006 Apr;7(4):265-75
16607289
Nat Rev Mol Cell Biol. 2013 Aug;14(8):467-73
23839578
J Cell Biol. 2008 Oct 20;183(2):223-39
18936248
Mol Cell Biol. 2009 Mar;29(6):1575-91
19114551
Nat Cell Biol. 2013 Mar;15(3):302-8
23434825
PLoS One. 2013 Dec 31;8(12):e84393
24391950
Diabetes. 2006 Sep;55(9):2571-8
16936206
Cell Metab. 2013 Oct 1;18(4):470-7
23954640
Nat Mater. 2014 Jun;13(6):631-7
24793358
In Vitro Cell Dev Biol Anim. 2000 Jan;36(1):38-44
10691039
Proteomics. 2013 Jan;13(1):22-4
23148064
Curr Biol. 2007 Jul 3;17(13):1151-6
17600709