Genetic backgrounds determine brown remodeling of white fat in rodents.
OBJECTIVE
Genetic background largely contributes to the complexity of metabolic responses and dysfunctions. Induction of brown adipose features in white fat, known as brown remodeling, has been appreciated as a promising strategy to offset the positive energy balance in obesity and further to improve metabolism. Here we address the effects of genetic background on this process.


METHODS
We investigated browning remodeling in a depot-specific manner by comparing the response of C57BL/6J, 129/Sv and FVB/NJ mouse strains to cold.


RESULTS
Surprisingly, 129/Sv and FVB/NJ mice showed distinct brown remodeling features despite their similar resistance to metabolic disorders in comparison to the obesity-prone C57BL/6J mice. FVB/NJ mice demonstrated a preference of brown remodeling in inguinal subcutaneous white adipose tissue (iWAT), whereas 129/Sv mice displayed robust brown remodeling in visceral epididymal fat (eWAT). We further compared gene expression in different depots by RNA-sequencing and identified Hoxc10 as a novel "brake" of brown remodeling in iWAT.


CONCLUSIONS
Rodent genetic background determines the brown remodeling of different white fat depots. This study provides new insights into the role of genetic variation in fat remodeling in susceptibility to metabolic diseases.
Department of Pathology and Cell Biology, Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Giulia
G
Ferrannini
Department of Pathology and Cell Biology, Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Maria
M
Namwanje
The Institute for Diabetes, Obesity, and Metabolism, The Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Bin
B
Fang
The Institute for Diabetes, Obesity, and Metabolism, The Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Manashree
M
Damle
Department of Pathology and Cell Biology, Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Dylan
D
Li
Department of Pathology and Cell Biology, Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Qiongming
Q
Liu
The Institute for Diabetes, Obesity, and Metabolism, The Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Mitchell A
MA
Lazar
Department of Pathology and Cell Biology, Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: lq2123@cumc.columbia.edu.
Li
L
Qiang
Brown remodeling; Browning brake; Cold exposure; Genetic background; Hoxc10; White adipose tissue
Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1244-53
20354155
Nat Med. 2013 Oct;19(10):1338-44
23995282
Nature. 2015 Apr 2;520(7545):57-62
25799988
Mol Cell Biol. 2008 Nov;28(22):6785-95
18794372
Nature. 2013 Nov 21;503(7476):410-3
24162845
Nat Med. 2012 Jun;18(6):918-25
22561685
Physiol Genomics. 2003 Jul 07;14 (2):139-47
12746468
Diabetes. 2014 Feb;63(2):514-25
24150604
Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2065-9
1848692
JAMA Intern Med. 2015 Aug;175(8):1412-3
26098405
Mol Cell Biol. 2005 Sep;25(18):8311-22
16135818
Proc Natl Acad Sci U S A. 2014 Sep 30;111(39):14289-94
25225406
Lancet. 2016 Apr 2;387(10026):1377-96
27115820
J Biol Chem. 2000 Nov 3;275(44):34486-92
10931824
Bioinformatics. 2009 May 1;25(9):1105-11
19289445
Genes Dev. 2012 Feb 1;26(3):271-81
22302939
J Clin Invest. 2014 Feb;124(2):515-27
24401271
Cell. 2012 Jul 20;150(2):366-76
22796012
Am J Physiol. 1994 Apr;266(4 Pt 2):R1371-82
7910436
Nat Biotechnol. 2010 May;28(5):511-5
20436464
Cell Metab. 2011 Sep 7;14 (3):324-38
21907139
J Health Econ. 2012 Jan;31(1):219-30
22094013
J Clin Invest. 2011 Jan;121(1):96-105
21123942
Biochim Biophys Acta. 2013 May;1831(5):950-9
23454374
Lancet. 2005 Sep 24-30;366(9491):1059-62
16182882
Nature. 2009 Aug 27;460(7259):1154-8
19641492
BMC Public Health. 2009 Mar 25;9:88
19320986
J Biol Chem. 2010 Mar 5;285(10 ):7153-64
20028987
J Clin Invest. 1998 Jul 15;102(2):412-20
9664083
Obesity (Silver Spring). 2016 Jan;24(1):51-9
26647900
Nat Cell Biol. 2013 Jun;15(6):659-67
23624403
J Lipid Res. 2007 Jan;48(1):41-51
17041251
Mol Cell. 2009 Sep 24;35(6):755-68
19782026
Front Endocrinol (Lausanne). 2016 Mar 02;7:19
26973598
Genomics. 2004 May;83(5):902-11
15081119
Cell. 2015 Jan 15;160(1-2):105-18
25579684
J Lipid Res. 2012 Apr;53(4):619-29
22271685
Cell Metab. 2015 Aug 4;22(2):219-27
26244931
Diabetes. 2004 Dec;53(12):3274-85
15561960
Science. 2010 May 28;328(5982):1158-61
20448152
Mol Metab. 2015 Mar 10;4(6):461-70
26042200
Cell Metab. 2005 Nov;2(5):283-95
16271529
Cell. 2015 Jul 2;162(1):33-44
26140591
PLoS One. 2012;7(11):e49452
23166672
Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8437-42
15155905
Biochim Biophys Acta. 2013 May;1831(5):960-8
23376694
Am J Physiol Endocrinol Metab. 2012 Jan 1;302(1):E19-31
21828341
Genes Dev. 2013 Feb 1;27(3):234-50
23388824
Endocrinology. 1997 Jan;138(1):405-13
8977430
Nucleic Acids Res. 2012 Jan;40(Database issue):D144-9
22080564
Metabolism. 1995 May;44(5):645-51
7752914
Cell Metab. 2012 Mar 7;15(3):395-404
22405074
Biochim Biophys Acta. 2014 Sep;1841(9):1345-52
24953778