title: Preserved glucose tolerance in high-fat-fed C57BL/6 mice transplanted with PPARgamma-/-, PPARdelta-/-, PPARgammadelta-/-, or LXRalphabeta-/- bone marrow.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, Molecular Biology Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Chaitra
authors.initials: C
authors.lastname: Marathe
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Bradley
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.forename: Lily
authors.initials: L
authors.lastname: Chao
authors.forename: Damien
authors.initials: D
authors.lastname: Wilpitz
authors.forename: Jon
authors.initials: J
authors.lastname: Salazar
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: 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
chemical_list: 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
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