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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.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.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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All PPAR mice had equivalent weight gain and exhibited reconstitution with myeloid cells derived from donor mice. A: Irradiated mice transplanted with wild-type, PPARγ−/−, PPARδ−/−, or PPARγδ−/− myeloid cells were challenged with a 60% fat diet. All groups of mice gained weight at similar rates. B: Thioglycollate-elicted wild-type and PPARγ−/− peritoneal macrophages were harvested from recipient mice to determine degree of reconstitution. PPARγ exon 2 could not be detected in PPARγ−/− macrophages (P < 0.05), whereas PPARγ exon 6 could be detected. Cells were harvested and pooled from four wild-type and three PPARγ−/− bone marrow transplant (BMT) mice. C: Wild-type and PPARγ−/− macrophages were treated with GW7845 overnight. PPARγ target genes (aP2 and ADRP) did not increase in expression as a result of ligand treatment in PPARγ−/− cells. Cells were harvested and pooled from four wild-type and three PPARγ−/− BMT mice. Error bars represent SEM.
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fig3: All PPAR mice had equivalent weight gain and exhibited reconstitution with myeloid cells derived from donor mice. A: Irradiated mice transplanted with wild-type, PPARγ−/−, PPARδ−/−, or PPARγδ−/− myeloid cells were challenged with a 60% fat diet. All groups of mice gained weight at similar rates. B: Thioglycollate-elicted wild-type and PPARγ−/− peritoneal macrophages were harvested from recipient mice to determine degree of reconstitution. PPARγ exon 2 could not be detected in PPARγ−/− macrophages (P < 0.05), whereas PPARγ exon 6 could be detected. Cells were harvested and pooled from four wild-type and three PPARγ−/− bone marrow transplant (BMT) mice. C: Wild-type and PPARγ−/− macrophages were treated with GW7845 overnight. PPARγ target genes (aP2 and ADRP) did not increase in expression as a result of ligand treatment in PPARγ−/− cells. Cells were harvested and pooled from four wild-type and three PPARγ−/− BMT mice. Error bars represent SEM.

Mentions: To investigate the impact of BM PPAR expression on systemic glucose metabolism in C57BL/6 mice, we used wild-type, PPARγ−/−, PPARδ−/−, or PPARγδ−/− BM (from mice more than 10 generations backcrossed to C57/BL6) to reconstitute irradiated wild-type mice. After recovery for 4 weeks, the mice were challenged with a 60% fat diet for an additional 14 weeks to cause obesity. All four groups of mice gained weight at a similar rate and had equivalent food intake during the course of the feeding (Fig. 3A; data not shown). To confirm the degree of BM reconstitution after 14 weeks of high-fat diet, we harvested thioglycollate-elicted peritoneal macrophages from PPARγ−/− and wild-type BMT-recipient mice. Real-time PCR verified that virtually all of the macrophages from PPARγ−/− BMT mice were derived from the donor cells, because PPARγ exon 2 was not expressed (Fig. 3B). We also tested whether the macrophages were responsive to ligand by examining PPAR target gene expression. As shown in Fig. 3C, expression of ADRP was induced by PPARγ ligand (GW7845) in cells from wild-type but not PPARγ−/− BMT mice. Basal expression of ADRP was also reduced in PPARγ- cells.


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)

All PPAR mice had equivalent weight gain and exhibited reconstitution with myeloid cells derived from donor mice. A: Irradiated mice transplanted with wild-type, PPARγ−/−, PPARδ−/−, or PPARγδ−/− myeloid cells were challenged with a 60% fat diet. All groups of mice gained weight at similar rates. B: Thioglycollate-elicted wild-type and PPARγ−/− peritoneal macrophages were harvested from recipient mice to determine degree of reconstitution. PPARγ exon 2 could not be detected in PPARγ−/− macrophages (P < 0.05), whereas PPARγ exon 6 could be detected. Cells were harvested and pooled from four wild-type and three PPARγ−/− bone marrow transplant (BMT) mice. C: Wild-type and PPARγ−/− macrophages were treated with GW7845 overnight. PPARγ target genes (aP2 and ADRP) did not increase in expression as a result of ligand treatment in PPARγ−/− cells. Cells were harvested and pooled from four wild-type and three PPARγ−/− BMT mice. Error bars represent SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: All PPAR mice had equivalent weight gain and exhibited reconstitution with myeloid cells derived from donor mice. A: Irradiated mice transplanted with wild-type, PPARγ−/−, PPARδ−/−, or PPARγδ−/− myeloid cells were challenged with a 60% fat diet. All groups of mice gained weight at similar rates. B: Thioglycollate-elicted wild-type and PPARγ−/− peritoneal macrophages were harvested from recipient mice to determine degree of reconstitution. PPARγ exon 2 could not be detected in PPARγ−/− macrophages (P < 0.05), whereas PPARγ exon 6 could be detected. Cells were harvested and pooled from four wild-type and three PPARγ−/− bone marrow transplant (BMT) mice. C: Wild-type and PPARγ−/− macrophages were treated with GW7845 overnight. PPARγ target genes (aP2 and ADRP) did not increase in expression as a result of ligand treatment in PPARγ−/− cells. Cells were harvested and pooled from four wild-type and three PPARγ−/− BMT mice. Error bars represent SEM.
Mentions: To investigate the impact of BM PPAR expression on systemic glucose metabolism in C57BL/6 mice, we used wild-type, PPARγ−/−, PPARδ−/−, or PPARγδ−/− BM (from mice more than 10 generations backcrossed to C57/BL6) to reconstitute irradiated wild-type mice. After recovery for 4 weeks, the mice were challenged with a 60% fat diet for an additional 14 weeks to cause obesity. All four groups of mice gained weight at a similar rate and had equivalent food intake during the course of the feeding (Fig. 3A; data not shown). To confirm the degree of BM reconstitution after 14 weeks of high-fat diet, we harvested thioglycollate-elicted peritoneal macrophages from PPARγ−/− and wild-type BMT-recipient mice. Real-time PCR verified that virtually all of the macrophages from PPARγ−/− BMT mice were derived from the donor cells, because PPARγ exon 2 was not expressed (Fig. 3B). We also tested whether the macrophages were responsive to ligand by examining PPAR target gene expression. As shown in Fig. 3C, expression of ADRP was induced by PPARγ ligand (GW7845) in cells from wild-type but not PPARγ−/− BMT mice. Basal expression of ADRP was also reduced in PPARγ- cells.

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.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.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