Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice.
OBJECTIVE
Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response.


METHODS
We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment.


RESULTS
We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization.


CONCLUSIONS
Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.
Institute of Metabolic Science, Metabolic Research Laboratories, and Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Xavier
X
Prieur
Crystal Y L
CY
Mok
Vidya R
VR
Velagapudi
Vanessa
V
Núñez
Lucía
L
Fuentes
David
D
Montaner
Ko
K
Ishikawa
Alberto
A
Camacho
Nuria
N
Barbarroja
Stephen
S
O'Rahilly
Jaswinder K
JK
Sethi
Joaquin
J
Dopazo
Matej
M
Orešič
Mercedes
M
Ricote
Antonio
A
Vidal-Puig
D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002458:Cell Fractionation; D002478:Cells, Cultured; D004032:Diet; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis
Nature. 2006 Dec 14;444(7121):860-7
17167474
Biochim Biophys Acta. 2010 Mar;1801(3):327-37
19796705
Biostatistics. 2003 Apr;4(2):249-64
12925520
Nucleic Acids Res. 2010 Jul;38(Web Server issue):W210-3
20478823
Biochem Soc Trans. 2008 Oct;36(Pt 5):935-40
18793164
Nature. 1998 Jan 1;391(6662):79-82
9422508
PLoS One. 2010 Apr 27;5(4):e10348
20436964
Diabetes. 2008 Dec;57(12):3239-46
18829989
PLoS Biol. 2008 Sep 23;6(9):e237
18816166
J Cell Biol. 2005 Oct 10;171(1):61-73
16203857
Biochim Biophys Acta. 2010 Mar;1801(3):207-8
20045080
Cell Metab. 2007 Aug;6(2):137-43
17681149
J Clin Invest. 2007 Jan;117(1):175-84
17200717
Cell Metab. 2008 Oct;8(4):301-9
18840360
Nat Med. 2009 Dec;15(12):1383-91
19966778
FEBS Lett. 2008 Jan 9;582(1):117-31
18037376
Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22504-9
20018750
Diabetes. 2007 Jan;56(1):16-23
17192460
Dis Model Mech. 2009 Nov-Dec;2(11-12):582-92
19841237
Nucleic Acids Res. 2008 Jan;36(Database issue):D480-4
18077471
Mol Cell Biol. 2009 Mar;29(6):1575-91
19114551
Stat Appl Genet Mol Biol. 2004;3:Article3
16646809
Bioinformatics. 2009 Jan 15;25(2):211-7
19038984
Bioinformatics. 2003 Jan 22;19(2):185-93
12538238
Crit Rev Immunol. 2001;21(5):399-425
11942557
J Lipid Res. 2007 Jun;48(6):1253-62
17374880
J Clin Invest. 2003 Dec;112(12):1796-808
14679176
Biochim Biophys Acta. 2010 Mar;1801(3):338-49
20056169