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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 and insulin levels exhibited no significant differences in insulin sensitivity. A two-way ANOVA test was used to determine significance. A: After 14 weeks on the diet, the four groups of PPAR mice were equally diabetic and similarly insulin resistant (P > 0.05). After the mice were fasted overnight, basal blood glucose levels were measured (0 min) before intraperitoneal administration of 2 g/kg glucose. Blood glucose was assessed every 30 min after the glucose bolus. B: A second glucose tolerance test performed after an additional 4 weeks yielded similar results (P > 0.05). C: Wild-type and PPARγ−/− mice were treated with rosiglitazone (30 mg/kg) for 8 days. A glucose tolerance test was performed as previously described. Rosiglitazone improved insulin sensitivity in both wild-type and PPARγ−/− mice, whereas vehicle treatment did not demonstrate a decrease in blood glucose levels in either group (P < 0.02). Error bars represent SEM.
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fig4: Glucose tolerance tests and insulin levels exhibited no significant differences in insulin sensitivity. A two-way ANOVA test was used to determine significance. A: After 14 weeks on the diet, the four groups of PPAR mice were equally diabetic and similarly insulin resistant (P > 0.05). After the mice were fasted overnight, basal blood glucose levels were measured (0 min) before intraperitoneal administration of 2 g/kg glucose. Blood glucose was assessed every 30 min after the glucose bolus. B: A second glucose tolerance test performed after an additional 4 weeks yielded similar results (P > 0.05). C: Wild-type and PPARγ−/− mice were treated with rosiglitazone (30 mg/kg) for 8 days. A glucose tolerance test was performed as previously described. Rosiglitazone improved insulin sensitivity in both wild-type and PPARγ−/− mice, whereas vehicle treatment did not demonstrate a decrease in blood glucose levels in either group (P < 0.02). Error bars represent SEM.

Mentions: After mice were on the diet for 14 weeks, we performed glucose tolerance tests to determine whether reconstitution with differing PPAR knockout macrophages would alter systemic metabolism. Mice clearly became glucose intolerant as a result of high-fat feeding; however, high-fat-fed mice lacking BM expression of PPARγ, PPARδ, or both on the C57BL/6 background showed no significant difference from controls (Fig. 4A). A second set of glucose tolerance tests performed 4 weeks later yielded similar results (Fig. 4B). Fasting serum insulin levels were also not significantly different between groups, as determined by ELISA (P > 0.05; data not shown).


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 and insulin levels exhibited no significant differences in insulin sensitivity. A two-way ANOVA test was used to determine significance. A: After 14 weeks on the diet, the four groups of PPAR mice were equally diabetic and similarly insulin resistant (P > 0.05). After the mice were fasted overnight, basal blood glucose levels were measured (0 min) before intraperitoneal administration of 2 g/kg glucose. Blood glucose was assessed every 30 min after the glucose bolus. B: A second glucose tolerance test performed after an additional 4 weeks yielded similar results (P > 0.05). C: Wild-type and PPARγ−/− mice were treated with rosiglitazone (30 mg/kg) for 8 days. A glucose tolerance test was performed as previously described. Rosiglitazone improved insulin sensitivity in both wild-type and PPARγ−/− mice, whereas vehicle treatment did not demonstrate a decrease in blood glucose levels in either group (P < 0.02). Error bars represent SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Glucose tolerance tests and insulin levels exhibited no significant differences in insulin sensitivity. A two-way ANOVA test was used to determine significance. A: After 14 weeks on the diet, the four groups of PPAR mice were equally diabetic and similarly insulin resistant (P > 0.05). After the mice were fasted overnight, basal blood glucose levels were measured (0 min) before intraperitoneal administration of 2 g/kg glucose. Blood glucose was assessed every 30 min after the glucose bolus. B: A second glucose tolerance test performed after an additional 4 weeks yielded similar results (P > 0.05). C: Wild-type and PPARγ−/− mice were treated with rosiglitazone (30 mg/kg) for 8 days. A glucose tolerance test was performed as previously described. Rosiglitazone improved insulin sensitivity in both wild-type and PPARγ−/− mice, whereas vehicle treatment did not demonstrate a decrease in blood glucose levels in either group (P < 0.02). Error bars represent SEM.
Mentions: After mice were on the diet for 14 weeks, we performed glucose tolerance tests to determine whether reconstitution with differing PPAR knockout macrophages would alter systemic metabolism. Mice clearly became glucose intolerant as a result of high-fat feeding; however, high-fat-fed mice lacking BM expression of PPARγ, PPARδ, or both on the C57BL/6 background showed no significant difference from controls (Fig. 4A). A second set of glucose tolerance tests performed 4 weeks later yielded similar results (Fig. 4B). Fasting serum insulin levels were also not significantly different between groups, as determined by ELISA (P > 0.05; data not shown).

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