A1 and A3 adenosine receptors (ARs) belong to the group of GPCRs that primarily couple to Gi/o protein and mediate adenosine’s biological actions. ARs are widely expressed in the body and regulate various metabolic functions. We generated mice lacking two ARs, Adora1-/-; Adora3-/- (double knockout [A1A3DKO]) to enable investigation of the role of Gi-coupled ARs on glucose metabolism. The Adora1-/- (A1KO), Adora3-/- (A3KO) and WT mice generated as littermates were used as controls. A1A3DKO mice showed no difference in body weight, glucose tolerance, insulin sensitivity, fed blood glucose and plasma insulin levels on regular chow (RC). Fasting blood glucose levels were reduced in A1KO and A1A3DKO mice compared to WT mice. No difference in body weight was observed between A1A3DKO and control groups on high fat diet (HFD). A1KO mice showed improved glucose tolerance compared to A3KO mice without any difference in insulin sensitivity. No difference in plasma insulin levels was observed between the groups. Fasting blood glucose levels were reduced in A1A3DKO mice and A1KO mice compared to WT and A3KO mice, respectively. We investigated the contribution of liver to the observed decrease in fasting blood glucose levels. Pyruvate tolerance test revealed decreased glucose output from the liver in A1KO and A1A3DKO mice. Expression levels of hepatic genes involved in gluconeogenesis, lipid uptake, lipogenesis and inflammation were reduced in A1KO and A1A3DKO mice. Activation of A1AR by specific agonist (MRS7469) increased the phosphorylation of c-Jun N-terminal Kinases (JNK). Increased hepatic glucose production because of Gi signaling-mediated JNK activation is well documented. Taken together, our data support the concept that A1AR antagonists may prove valuable in enhancing whole-body glucose homeostasis by improving hepatic metabolism and could be beneficial in diabetes treatment.


S. Jain: None. D.K. Tosh: None. M. Reitman: None. K.A. Jacobson: None.

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