Limits...
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.

Show MeSH

Related in: MedlinePlus

Classical M2 gene expression is not absolutely dependent on PPAR expression in BM-derived macrophages. Wild-type, PPARγ−/−, PPARδ−/−, and PPARγδ−/− BM cells were harvested, differentiated into macrophages, and treated with IL-4 or IL-13 (10 ng/ml each) overnight. Expression of M2 genes was analyzed to determine impact of PPARγ, PPARδ, or both PPARγ and PPARδ deficiencies. The presented data are representative of two independent experiments. Error bars represent SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2636915&req=5

fig7: Classical M2 gene expression is not absolutely dependent on PPAR expression in BM-derived macrophages. Wild-type, PPARγ−/−, PPARδ−/−, and PPARγδ−/− BM cells were harvested, differentiated into macrophages, and treated with IL-4 or IL-13 (10 ng/ml each) overnight. Expression of M2 genes was analyzed to determine impact of PPARγ, PPARδ, or both PPARγ and PPARδ deficiencies. The presented data are representative of two independent experiments. Error bars represent SEM.

Mentions: It has been previously reported that alternative activation of BALB/C macrophages relies significantly on appropriate PPAR signaling (22, 24). Studies have demonstrated that PPARγ-deficient macrophages express low levels of M2 marker genes and are not effectively alternatively activated (22). As a result, these cells may be more inflammatory and may act as contributors to worsened insulin sensitivity. To test whether PPARγ−/− or PPARδ−/− macrophages from C57BL/6 mice also expressed reduced levels of alternative activation marker genes, we stimulated BM-derived macrophages with cytokines that upregulate Th-2 response, such as IL-4 or IL-13 (25). We found that the absence of PPARs did not compromise M2 inflammatory responses under our experimental conditions. Expression of classical M2 marker genes such as Chi3l3, Pdcd1lg2, and Clec7a (26, 27) in response to IL-4 or IL-13 in PPARγ−/−, PPARδ−/−, or PPARγδ−/− macrophages was not significantly different from wild-type macrophages (Fig. 7). However, the loss of PPARγ in macrophages resulted in lower expression of arginase I (ArgI), a primary M2 marker gene (28), in response to IL-4 or IL-13 stimulation. ArgI has been previously described as a direct PPARγ and PPARδ target gene, and this may explain the reduced ArgI expression in PPARγ-deficient macrophages (22, 29). Interestingly, ArgI expression was unique in its dependence on PPARγ for induction; the expression of the remaining M2 marker genes we tested was not altered by the loss of PPARs.


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)

Classical M2 gene expression is not absolutely dependent on PPAR expression in BM-derived macrophages. Wild-type, PPARγ−/−, PPARδ−/−, and PPARγδ−/− BM cells were harvested, differentiated into macrophages, and treated with IL-4 or IL-13 (10 ng/ml each) overnight. Expression of M2 genes was analyzed to determine impact of PPARγ, PPARδ, or both PPARγ and PPARδ deficiencies. The presented data are representative of two independent experiments. Error bars represent SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: Classical M2 gene expression is not absolutely dependent on PPAR expression in BM-derived macrophages. Wild-type, PPARγ−/−, PPARδ−/−, and PPARγδ−/− BM cells were harvested, differentiated into macrophages, and treated with IL-4 or IL-13 (10 ng/ml each) overnight. Expression of M2 genes was analyzed to determine impact of PPARγ, PPARδ, or both PPARγ and PPARδ deficiencies. The presented data are representative of two independent experiments. Error bars represent SEM.
Mentions: It has been previously reported that alternative activation of BALB/C macrophages relies significantly on appropriate PPAR signaling (22, 24). Studies have demonstrated that PPARγ-deficient macrophages express low levels of M2 marker genes and are not effectively alternatively activated (22). As a result, these cells may be more inflammatory and may act as contributors to worsened insulin sensitivity. To test whether PPARγ−/− or PPARδ−/− macrophages from C57BL/6 mice also expressed reduced levels of alternative activation marker genes, we stimulated BM-derived macrophages with cytokines that upregulate Th-2 response, such as IL-4 or IL-13 (25). We found that the absence of PPARs did not compromise M2 inflammatory responses under our experimental conditions. Expression of classical M2 marker genes such as Chi3l3, Pdcd1lg2, and Clec7a (26, 27) in response to IL-4 or IL-13 in PPARγ−/−, PPARδ−/−, or PPARγδ−/− macrophages was not significantly different from wild-type macrophages (Fig. 7). However, the loss of PPARγ in macrophages resulted in lower expression of arginase I (ArgI), a primary M2 marker gene (28), in response to IL-4 or IL-13 stimulation. ArgI has been previously described as a direct PPARγ and PPARδ target gene, and this may explain the reduced ArgI expression in PPARγ-deficient macrophages (22, 29). Interestingly, ArgI expression was unique in its dependence on PPARγ for induction; the expression of the remaining M2 marker genes we tested was not altered by the loss of PPARs.

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