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The macrophage A2B adenosine receptor regulates tissue insulin sensitivity.

Johnston-Cox H, Eisenstein AS, Koupenova M, Carroll S, Ravid K - PLoS ONE (2014)

Bottom Line: High fat diet (HFD)-induced type 2 diabetes continues to be an epidemic with significant risk for various pathologies.As the A2bAR is expressed in different tissues, here, we provide the first lead to cellular mechanism by demonstrating that the receptor's influence on tissue insulin sensitivity is mediated via its expression in macrophages.The molecular mechanism for this effect involves A2bAR-mediated changes in cyclic adenosine monophosphate in macrophages, reducing the expression and release of inflammatory cytokines, which downregulate insulin receptor-2.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.

ABSTRACT
High fat diet (HFD)-induced type 2 diabetes continues to be an epidemic with significant risk for various pathologies. Previously, we identified the A2b adenosine receptor (A2bAR), an established regulator of inflammation, as a regulator of HFD-induced insulin resistance. In particular, HFD was associated with vast upregulation of liver A2bAR in control mice, and while mice lacking this receptor showed augmented liver inflammation and tissue insulin resistance. As the A2bAR is expressed in different tissues, here, we provide the first lead to cellular mechanism by demonstrating that the receptor's influence on tissue insulin sensitivity is mediated via its expression in macrophages. This was shown using a newly generated transgenic mouse model expressing the A2bAR gene in the macrophage lineage on an otherwise A2bAR background. Reinstatement of macrophage A2bAR expression in A2bAR mice fed HFD restored insulin tolerance and tissue insulin signaling to the level of control mice. The molecular mechanism for this effect involves A2bAR-mediated changes in cyclic adenosine monophosphate in macrophages, reducing the expression and release of inflammatory cytokines, which downregulate insulin receptor-2. Thus, our results illustrate that macrophage A2bAR signaling is needed and sufficient for relaying the protective effect of the A2bAR against HFD-induced tissue inflammation and insulin resistance in mice.

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Proposed mechanism for preventative action of A2bAR on insulin signaling.Macrophage signaling through the A2bAR reduces TNF-α expression [31], [39]–[43]. Reduced cytokine expression prevents the inflammation-induced decrease in tissue IRS-2 by the direct action of inflammatory cytokines [11]–[13]. As a result, macrophage A2bAR signaling enables appropriate tissue insulin signaling.
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pone-0098775-g009: Proposed mechanism for preventative action of A2bAR on insulin signaling.Macrophage signaling through the A2bAR reduces TNF-α expression [31], [39]–[43]. Reduced cytokine expression prevents the inflammation-induced decrease in tissue IRS-2 by the direct action of inflammatory cytokines [11]–[13]. As a result, macrophage A2bAR signaling enables appropriate tissue insulin signaling.

Mentions: Taken together, our findings suggest that the monocytic lineage is the major cellular player in conveying A2bAR-induced protection against insulin resistance. Our findings suggest that under HFD, signaling through macrophage A2bAR reduces inflammatory cytokine expression via increased cAMP levels, which leads to augmented levels of IRS-2 in adipocytes and hepatocytes, ultimately leading to improved insulin signaling as outlined in Figure 9.


The macrophage A2B adenosine receptor regulates tissue insulin sensitivity.

Johnston-Cox H, Eisenstein AS, Koupenova M, Carroll S, Ravid K - PLoS ONE (2014)

Proposed mechanism for preventative action of A2bAR on insulin signaling.Macrophage signaling through the A2bAR reduces TNF-α expression [31], [39]–[43]. Reduced cytokine expression prevents the inflammation-induced decrease in tissue IRS-2 by the direct action of inflammatory cytokines [11]–[13]. As a result, macrophage A2bAR signaling enables appropriate tissue insulin signaling.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043770&req=5

pone-0098775-g009: Proposed mechanism for preventative action of A2bAR on insulin signaling.Macrophage signaling through the A2bAR reduces TNF-α expression [31], [39]–[43]. Reduced cytokine expression prevents the inflammation-induced decrease in tissue IRS-2 by the direct action of inflammatory cytokines [11]–[13]. As a result, macrophage A2bAR signaling enables appropriate tissue insulin signaling.
Mentions: Taken together, our findings suggest that the monocytic lineage is the major cellular player in conveying A2bAR-induced protection against insulin resistance. Our findings suggest that under HFD, signaling through macrophage A2bAR reduces inflammatory cytokine expression via increased cAMP levels, which leads to augmented levels of IRS-2 in adipocytes and hepatocytes, ultimately leading to improved insulin signaling as outlined in Figure 9.

Bottom Line: High fat diet (HFD)-induced type 2 diabetes continues to be an epidemic with significant risk for various pathologies.As the A2bAR is expressed in different tissues, here, we provide the first lead to cellular mechanism by demonstrating that the receptor's influence on tissue insulin sensitivity is mediated via its expression in macrophages.The molecular mechanism for this effect involves A2bAR-mediated changes in cyclic adenosine monophosphate in macrophages, reducing the expression and release of inflammatory cytokines, which downregulate insulin receptor-2.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.

ABSTRACT
High fat diet (HFD)-induced type 2 diabetes continues to be an epidemic with significant risk for various pathologies. Previously, we identified the A2b adenosine receptor (A2bAR), an established regulator of inflammation, as a regulator of HFD-induced insulin resistance. In particular, HFD was associated with vast upregulation of liver A2bAR in control mice, and while mice lacking this receptor showed augmented liver inflammation and tissue insulin resistance. As the A2bAR is expressed in different tissues, here, we provide the first lead to cellular mechanism by demonstrating that the receptor's influence on tissue insulin sensitivity is mediated via its expression in macrophages. This was shown using a newly generated transgenic mouse model expressing the A2bAR gene in the macrophage lineage on an otherwise A2bAR background. Reinstatement of macrophage A2bAR expression in A2bAR mice fed HFD restored insulin tolerance and tissue insulin signaling to the level of control mice. The molecular mechanism for this effect involves A2bAR-mediated changes in cyclic adenosine monophosphate in macrophages, reducing the expression and release of inflammatory cytokines, which downregulate insulin receptor-2. Thus, our results illustrate that macrophage A2bAR signaling is needed and sufficient for relaying the protective effect of the A2bAR against HFD-induced tissue inflammation and insulin resistance in mice.

Show MeSH
Related in: MedlinePlus