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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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Glucose tolerance tests in wild-type and LXRαβ−/− mice revealed no difference in blood glucose levels. A two-way ANOVA test was used to determine significance. A: Wild-type and LXRαβ−/− mice were challenged with a 60% fat diet for 14 weeks. After mice were fasted overnight, basal blood glucose levels were measured. Glucose (2 g/kg) was administered, then blood glucose was assessed every 30 min for 2 h. Both groups of mice were equally insulin resistant (P > 0.05). B: A second glucose tolerance test was performed after an additional 4 weeks as previously described. Similar results were obtained (P > 0.05). Error bars represent SEM.
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fig6: Glucose tolerance tests in wild-type and LXRαβ−/− mice revealed no difference in blood glucose levels. A two-way ANOVA test was used to determine significance. A: Wild-type and LXRαβ−/− mice were challenged with a 60% fat diet for 14 weeks. After mice were fasted overnight, basal blood glucose levels were measured. Glucose (2 g/kg) was administered, then blood glucose was assessed every 30 min for 2 h. Both groups of mice were equally insulin resistant (P > 0.05). B: A second glucose tolerance test was performed after an additional 4 weeks as previously described. Similar results were obtained (P > 0.05). Error bars represent SEM.

Mentions: After mice were on on a high-fat diet for 14 weeks, a glucose tolerance test was performed. Similar to the results obtained with the PPAR BM transplants, we observed no difference in glucose tolerance or insulin levels between mice transplanted with wild-type or LXRαβ−/− BM (Fig. 6A; data not shown). A second independent test performed 4 weeks later showed similar results (Fig. 6B). These observations indicate that despite their anti-inflammatory effects, loss of LXR expression in the BM does not exert a major influence on glucose tolerance in high-fat-fed mice.


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)

Glucose tolerance tests in wild-type and LXRαβ−/− mice revealed no difference in blood glucose levels. A two-way ANOVA test was used to determine significance. A: Wild-type and LXRαβ−/− mice were challenged with a 60% fat diet for 14 weeks. After mice were fasted overnight, basal blood glucose levels were measured. Glucose (2 g/kg) was administered, then blood glucose was assessed every 30 min for 2 h. Both groups of mice were equally insulin resistant (P > 0.05). B: A second glucose tolerance test was performed after an additional 4 weeks as previously described. Similar results were obtained (P > 0.05). Error bars represent SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: Glucose tolerance tests in wild-type and LXRαβ−/− mice revealed no difference in blood glucose levels. A two-way ANOVA test was used to determine significance. A: Wild-type and LXRαβ−/− mice were challenged with a 60% fat diet for 14 weeks. After mice were fasted overnight, basal blood glucose levels were measured. Glucose (2 g/kg) was administered, then blood glucose was assessed every 30 min for 2 h. Both groups of mice were equally insulin resistant (P > 0.05). B: A second glucose tolerance test was performed after an additional 4 weeks as previously described. Similar results were obtained (P > 0.05). Error bars represent SEM.
Mentions: After mice were on on a high-fat diet for 14 weeks, a glucose tolerance test was performed. Similar to the results obtained with the PPAR BM transplants, we observed no difference in glucose tolerance or insulin levels between mice transplanted with wild-type or LXRαβ−/− BM (Fig. 6A; data not shown). A second independent test performed 4 weeks later showed similar results (Fig. 6B). These observations indicate that despite their anti-inflammatory effects, loss of LXR expression in the BM does not exert a major influence on glucose tolerance in high-fat-fed mice.

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