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Preserved glucose tolerance in high-fat-fed C57BL/6 mice transplanted with PPARgamma-/-, PPARdelta-/-, PPARgammadelta-/-, or LXRalphabeta-/- bone marrow.

Marathe C, Bradley MN, Hong C, Chao L, Wilpitz D, Salazar J, Tontonoz P - J. Lipid Res. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Molecular Biology Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.

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.

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Recipient mice showed equivalent weight gain and exhibited efficient reconstitution with wild-type or LXR- donor bone marrow (BM). A: Wild-type and LXRαβ−/− mice gained weight at similar rates on a 60% fat diet. B: Thioglycollate-elicted wild-type and LXRαβ−/− peritoneal macrophages were harvested from recipient mice to determine degree of reconstitution. Wild-type and LXRαβ−/− macrophages were pretreated with GW3965 or T1317 (1 μM) and then stimulated with LPS (10 ng/ml) for 6 h. The LXRαβ target gene, ABCA1, did not increase in expression as a result of ligand treatment in LXRαβ−/− cells. Furthermore, LXRαβ−/− cells failed to repress TNFα gene expression. Wild-type cells treated with LXR ligand were able to exert anti-inflammatory control. Error bars represent SEM.
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fig5: Recipient mice showed equivalent weight gain and exhibited efficient reconstitution with wild-type or LXR- donor bone marrow (BM). A: Wild-type and LXRαβ−/− mice gained weight at similar rates on a 60% fat diet. B: Thioglycollate-elicted wild-type and LXRαβ−/− peritoneal macrophages were harvested from recipient mice to determine degree of reconstitution. Wild-type and LXRαβ−/− macrophages were pretreated with GW3965 or T1317 (1 μM) and then stimulated with LPS (10 ng/ml) for 6 h. The LXRαβ target gene, ABCA1, did not increase in expression as a result of ligand treatment in LXRαβ−/− cells. Furthermore, LXRαβ−/− cells failed to repress TNFα gene expression. Wild-type cells treated with LXR ligand were able to exert anti-inflammatory control. Error bars represent SEM.

Mentions: Previous work has established that both LXRα and LXRβ are expressed at high levels in macrophages, and both isotypes have strong anti-inflammatory effects (19). As shown in Fig. 2B, the anti-inflammatory effects of LXRs are especially prominent in vitro. We hypothesized that loss of LXR receptor expression in BM cells might exacerbate inflammatory signaling in vivo and impact glucose metabolism. We therefore transplanted BM cells from wild-type and LXRαβ−/− mice into irradiated wild-type recipients. As with the mice used for PPAR studies, the animals used for these experiments were also more than 10 generations backcrossed to C57BL/6 mice. After 4 weeks of recovery, the BMT mice were challenged with a 60% fat diet to induce obesity and insulin resistance. All groups consumed similar amounts of food and gained weight at similar rates (Fig. 5A). We confirmed that the reconstituted animals had been repopulated with LXRαβ−/− BM by harvesting thioglycollate-elicted peritoneal macrophages and performing real-time PCR to examine the expression of LXRs and their downstream target genes. As expected, LXR ligands (GW3965 and T1317) induced expression of ABCA1 in wild-type but not in LXRαβ−/− BMT cells (Fig. 5B). We also verified that LXRs had maintained their anti-inflammatory abilities after reconstitution by stimulating macrophages with LPS in the presence or absence of LXR ligand. Indeed, LXR ligand repressed expression of TNFα in wild-type but not LXR- BM recipients (Fig. 5B).


Preserved glucose tolerance in high-fat-fed C57BL/6 mice transplanted with PPARgamma-/-, PPARdelta-/-, PPARgammadelta-/-, or LXRalphabeta-/- bone marrow.

Marathe C, Bradley MN, Hong C, Chao L, Wilpitz D, Salazar J, Tontonoz P - J. Lipid Res. (2008)

Recipient mice showed equivalent weight gain and exhibited efficient reconstitution with wild-type or LXR- donor bone marrow (BM). A: Wild-type and LXRαβ−/− mice gained weight at similar rates on a 60% fat diet. B: Thioglycollate-elicted wild-type and LXRαβ−/− peritoneal macrophages were harvested from recipient mice to determine degree of reconstitution. Wild-type and LXRαβ−/− macrophages were pretreated with GW3965 or T1317 (1 μM) and then stimulated with LPS (10 ng/ml) for 6 h. The LXRαβ target gene, ABCA1, did not increase in expression as a result of ligand treatment in LXRαβ−/− cells. Furthermore, LXRαβ−/− cells failed to repress TNFα gene expression. Wild-type cells treated with LXR ligand were able to exert anti-inflammatory control. Error bars represent SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2636915&req=5

fig5: Recipient mice showed equivalent weight gain and exhibited efficient reconstitution with wild-type or LXR- donor bone marrow (BM). A: Wild-type and LXRαβ−/− mice gained weight at similar rates on a 60% fat diet. B: Thioglycollate-elicted wild-type and LXRαβ−/− peritoneal macrophages were harvested from recipient mice to determine degree of reconstitution. Wild-type and LXRαβ−/− macrophages were pretreated with GW3965 or T1317 (1 μM) and then stimulated with LPS (10 ng/ml) for 6 h. The LXRαβ target gene, ABCA1, did not increase in expression as a result of ligand treatment in LXRαβ−/− cells. Furthermore, LXRαβ−/− cells failed to repress TNFα gene expression. Wild-type cells treated with LXR ligand were able to exert anti-inflammatory control. Error bars represent SEM.
Mentions: Previous work has established that both LXRα and LXRβ are expressed at high levels in macrophages, and both isotypes have strong anti-inflammatory effects (19). As shown in Fig. 2B, the anti-inflammatory effects of LXRs are especially prominent in vitro. We hypothesized that loss of LXR receptor expression in BM cells might exacerbate inflammatory signaling in vivo and impact glucose metabolism. We therefore transplanted BM cells from wild-type and LXRαβ−/− mice into irradiated wild-type recipients. As with the mice used for PPAR studies, the animals used for these experiments were also more than 10 generations backcrossed to C57BL/6 mice. After 4 weeks of recovery, the BMT mice were challenged with a 60% fat diet to induce obesity and insulin resistance. All groups consumed similar amounts of food and gained weight at similar rates (Fig. 5A). We confirmed that the reconstituted animals had been repopulated with LXRαβ−/− BM by harvesting thioglycollate-elicted peritoneal macrophages and performing real-time PCR to examine the expression of LXRs and their downstream target genes. As expected, LXR ligands (GW3965 and T1317) induced expression of ABCA1 in wild-type but not in LXRαβ−/− BMT cells (Fig. 5B). We also verified that LXRs had maintained their anti-inflammatory abilities after reconstitution by stimulating macrophages with LPS in the presence or absence of LXR ligand. Indeed, LXR ligand repressed expression of TNFα in wild-type but not LXR- BM recipients (Fig. 5B).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Molecular Biology Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.

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.

Show MeSH
Related in: MedlinePlus