Diabetes 2013 Aug-16

 

The A2b adenosine receptor modulates glucose homeostasis and obesity.

PLoS One. 2012;7(7):e40584.

Johnston-Cox H, Koupenova M, Yang D, Corkey B, Gokce N, Farb MG, LeBrasseur N, Ravid K.

Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.

PMID: 22848385

 

Background: High fat diet and its induced changes in glucose homeostasis, inflammation and obesity continue to be an epidemic in developed countries. The A2b adenosine receptor (A2bAR) is known to regulate inflammation. We used a diet-induced obesity murine knockout model to investigate the role of this receptor in mediating metabolic homeostasis, and correlated our findings in obese patient samples.

Methodology and Results: Administration of high fat, high cholesterol diet (HFD) for sixteen weeks vastly upregulated the expression of the A2bAR in control mice, and particularly in the liver. A2bAR knockout (KO) mice under a HFD developed greater obesity and hallmarks of type 2 diabetes (T2D), assessed by delayed glucose clearance and augmented insulin levels compared to matching control mice. This is indicative that this receptor plays an important role in glucose and insulin homeostatis under HFD. We identified a novel link between the expression of A2bAR, insulin receptor substrate 2 (IRS-2), and insulin signaling, determined by Western blotting for IRS-2 and tissue Akt phosphorylation, an established read-out for tissue insulin sensitivity. The latter is impaired in tissues of A2bAR KO mice, along with a greater inflammatory state. Additional mechanisms involved include A2bAR regulation of SREBP-1 expression, an important regulator of liver lipid synthesis, and a repressor of IRS-2. Importantly, pharmacological activation of the A2bAR by injection of the A2bAR specific ligand, BAY 60-6583, for four weeks post HFD restores IRS-2 levels, and ameliorates T2D. In obese human subjects, A2bAR expression in subcutaneous fat correlates strongly with IRS-2 expression.

Conclusion: Our study elucidates a role for the A2bAR in maintenance of glucose and insulin homeostasis, modulation of inflammatory mediated events, and lipid metabolism under HFD. We establish a role for A2bAR in the regulation of IRS-2 expression and effects on downstream insulin signaling. In absence of the A2bAR, elevated plasma and tissue inflammatory markers contribute to impaired insulin response, while pharmacological activation of the A2bAR modulates chronic inflammation and restores IRS-2 signaling. The translational value of this receptor is further enhanced with data that shows a positive association between the A2bAR and BMI, parameters of obesity (e.g. waist and hip circumference) and IRS-2 in subcutaneous fat samples obtained from obese patients. It is of interest to study if activation of the A2bAR in T2D patients can improve insulin resistance and inflammatory parameters. It is important to emphasize that the systemic protective effect of the A2bAR were observed under HFD; under conditions the receptor is upregulated in tissues in which it is not typically expressed. The effect of A2bAR and its ligands, of course, could be different under conditions of regular diet.

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