An allosteric modulator of the adenosine A1 receptor potentiates the antilipolytic effect in rat adipose tissue

The adenosine A1 receptor plays important roles in tuning free fatty acid (FFA) levels and represents an attractive target for metabolic disorders. Though remarkable progress has been achieved in the exploitation of effective (orthosteric) A1 receptor agonists in modulating aberrant FFA levels, the effect of A1 receptor allosteric modu-lation on lipid homeostasis is less investigated. Herein we sought to explore the effect of an allosteric modulator on the action of an A1 receptor orthosteric agonist in regulating the lipolytic process in vitro and in vivo. We examined the binding kinetics of a selective A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) in the absence or presence of an allosteric modulator (2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluoromethyl)-phenyl] methanone (PD81,723) on rat adipocyte membranes. We also examined the allosteric effects of PD81,723 on mediating the CCPA-induced inhibition of cAMP accumulation, HSL (hormone-sensitive lipase) phosphorylation and FFA production in in vitro and in vivo models. Our results demonstrated that PD81,723 slowed down the dissociation of CCPA from the A1 receptor, which, consequently, potentiated the antilipolytic action of CCPA through downregulating the cAMP/HSL pathway. Our study exemplified the application of A1 receptor allosteric modulators as an alternative for metabolic disease treatments.

Automated summary

The adenosine A1 receptor is an important target for metabolic disorders and plays a significant role in regulating free fatty acid levels. This study examined the effect of an allosteric modulator on the action of an A1 receptor agonist in regulating lipolysis. The results showed that the allosteric modulator enhanced the antilipolytic action of the agonist by slowing down its dissociation from the receptor and downregulating the cAMP/HSL pathway. This study highlights the potential application of A1 receptor allosteric modulators in the treatment of metabolic diseases.