Involvement of the metabolic sensor GPR81 in cardiovascular control
Kristina Wallenius, Pia Thalén, Jan-Arne Björkman, Petra Johannesson, John Wiseman, Gerhard Böttcher, Ola Fjellström, Nicholas D. Oakes
Kristina Wallenius, Pia Thalén, Jan-Arne Björkman, Petra Johannesson, John Wiseman, Gerhard Böttcher, Ola Fjellström, Nicholas D. Oakes
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Research Article Cardiology Metabolism

Involvement of the metabolic sensor GPR81 in cardiovascular control

Abstract

GPR81 is a receptor for the metabolic intermediate lactate with an established role in regulating adipocyte lipolysis. Potentially novel GPR81 agonists were identified that suppressed fasting plasma free fatty acid levels in rodents and in addition improved insulin sensitivity in mouse models of insulin resistance and diabetes. Unexpectedly, the agonists simultaneously induced hypertension in rodents, including wild-type, but not GPR81-deficient mice. Detailed cardiovascular studies in anesthetized dogs showed that the pressor effect was associated with heterogenous effects on vascular resistance among the measured tissues: increasing in the kidney while remaining unchanged in hindlimb and heart. Studies in rats revealed that the pressor effect could be blocked, and the renal resistance effect at least partially blocked, with pharmacological antagonism of endothelin receptors. In situ hybridization localized GPR81 to the microcirculation, notably afferent arterioles of the kidney. In conclusion, these results provide evidence for a potentially novel role of GPR81 agonism in blood pressure control and regulation of renal vascular resistance including modulation of a known vasoeffector mechanism, the endothelin system. In addition, support is provided for the concept of fatty acid lowering as a means of improving insulin sensitivity.

Authors

Kristina Wallenius, Pia Thalén, Jan-Arne Björkman, Petra Johannesson, John Wiseman, Gerhard Böttcher, Ola Fjellström, Nicholas D. Oakes

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Figure 4

The GPR81 agonist, AZ1, improves insulin sensitivity in diet-induced obese (DIO) mice.

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The GPR81 agonist, AZ1, improves insulin sensitivity in diet-induced obe...
Male mice, fed a high-fat (60% calories) diet for 15 weeks, were daily dosed for 3 weeks by oral gavage, with either vehicle or AZ1 (20 μmol/kg), at the beginning of the dark cycle. Responses to an oral glucose challenge (1 g/kg), given in the 4-hour fasted state at t = 0, are shown for plasma glucose (A) and for plasma insulin (B). Corresponding areas under the curves (AUC), between 0 and 120 minutes, for (C) plasma glucose (mM × h) and (D) insulin (nM × h). Results shown as the mean ± SEM (A and B) or individual data points together with the mean ± SEM (C and D). **P < 0.01 versus vehicle (Student’s t test, n = 8/group).