Preserved glucose tolerance in high-fat-fed C57BL/6 mice transplanted with PPARgamma-/-, PPARdelta-/-, PPARgammadelta-/-, or LXRalphabeta-/- bone marrow.
Macrophage lipid metabolism and inflammatory responses are both regulated by the nuclear receptors PPAR and LXR. Emerging links between inflammation and metabolic disease progression suggest that PPAR and LXR signaling may alter macrophage function and thereby impact systemic metabolism. In this study, the function of macrophage PPAR and LXR in Th1-biased C57BL/6 mice was tested using a bone marrow transplantation approach with PPARgamma(-/-), PPARdelta(-/-), PPARgammadelta(-/-), and LXRalphabeta(-/-) cells. Despite their inhibitory effects on inflammatory gene expression, loss of PPARs or LXRs in macrophages did not exert major effects on obesity or glucose tolerance induced by a high-fat diet. Treatment with rosiglitazone effectively improved glucose tolerance in mice lacking macrophage PPARgamma, suggesting that cell types other than macrophages are the primary mediators of the anti-diabetic effects of PPARgamma agonists in our model system. C57BL/6 macrophages lacking PPARs or LXRs exhibited normal expression of most alternative activation gene markers, indicating that macrophage alternative activation is not absolutely dependent on these receptors in the C57BL/6 background under the conditions used here. These studies suggest that genetic background may be an important modifier of nuclear receptor effects in macrophages. Our results do not exclude a contribution of macrophage PPAR and LXR expression to systemic metabolism in certain contexts, but these factors do not appear to be dominant contributors to glucose tolerance in a high-fat-fed Th1-biased bone marrow transplant model.
Marathe
Chaitra
C
Howard Hughes Medical Institute, Molecular Biology Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
Bradley
Michelle N
MN
Hong
Cynthia
C
Chao
Lily
L
Wilpitz
Damien
D
Salazar
Jon
J
Tontonoz
Peter
P
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D050260:Carbohydrate Metabolism / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage*; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D047494:PPAR delta / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D018417:Th1 Cells / Q000637:transplantation
D004268:DNA-Binding Proteins; D004041:Dietary Fats; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047494:PPAR delta; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear
Nature. 2006 Dec 14;444(7121):860-7
17167474
Cell Metab. 2007 Aug;6(2):137-43
17681149
Nature. 1997 Oct 9;389(6651):610-4
9335502
Mol Cell Biol. 2001 Nov;21(22):7558-68
11604492
Science. 1993 Jan 1;259(5091):87-91
7678183
Science. 2003 Oct 17;302(5644):453-7
12970571
J Clin Invest. 2007 Jun;117(6):1658-69
17525798
Nat Med. 2005 Feb;11(2):191-8
15685170
BMC Immunol. 2002 Jul 04;3:7
12098359
Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7265-70
12756299
Nat Rev Immunol. 2003 Jan;3(1):23-35
12511873
J Clin Invest. 2003 Dec;112(12):1821-30
14679177
J Immunol. 2003 Nov 1;171(9):4569-73
14568930
Mol Endocrinol. 2008 Jun;22(6):1394-402
18323470
Cell Metab. 2008 Jun;7(6):485-95
18522830
Nature. 1996 Oct 31;383(6603):787-93
8893001
Nature. 1998 Jan 1;391(6662):79-82
9422508
J Clin Invest. 1995 May;95(5):2409-15
7738205
J Intern Med. 2007 Oct;262(4):408-14
17875176
Nature. 1998 Jan 1;391(6662):82-6
9422509
Diabetes. 2007 Jan;56(1):16-23
17192460
Science. 2001 Aug 31;293(5535):1673-7
11533494
Nature. 2007 Jun 28;447(7148):1116-20
17515919
J Clin Invest. 2006 Jun;116(6):1494-505
16691291
Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5336-41
12697896
J Clin Invest. 2005 May;115(5):1111-9
15864338
Nat Med. 2003 Feb;9(2):213-9
12524534
J Biol Chem. 2006 Sep 8;281(36):26602-14
16809344
J Clin Invest. 2003 Dec;112(12):1796-808
14679176
Cell Metab. 2008 Jun;7(6):496-507
18522831