AdipoR1 and AdipoR2 contain seven-trans membrane Domains. But to be structurally and functionally distinct from G-protein-coupled receptor. It is reported that AdipoR1 activates the AMPK pathways and AdipoR2 activates the PPAR-a pathways. AdipoR1 and AdipoR2 serve as the major receptors for adiponectin in vivo.

In this article, we will introduce an orally active adiponectin receptor (AdipoR) agonist, AdipoRon.

AdipoRon binds to AdipoR1 and AdipoR2 with Kds of 1.8 and 3.1 μM, respectively.

At concentration 50 nM to 50 μM, AdipoRon increases AMPK phosphorylation via AdipoR1. In the L02 cells, AdipoRon dose-dependently attenuates the expression of TNF-α and TGF-β1. Additionally, AdipoRon exhibits significant and dosage-dependent growth suppression on macrophages.

What’s more, AdipoRon treatment significantly improves cardiac functional recovery after reperfusion. And it inhibits post-MI apoptosis.

As adiponectin is vasoprotective via NO-mediated signaling. AdipoRon similarly exerts potentially beneficial vasodilator effects.

As a result, AdipoRon exerts vasodilation by mechanisms distinct to adiponectin. Additionally, it induces vasorelaxation without a marked decrease in VSMCs. In the skeletal muscle of db/db mice, AdipoRon significantly increases the expression levels of genes involved in mitochondrial biogenesis functions and DNA content. Additionally, it also decreases Acadm and Sod2 expression.

AdipoRon causes significant phosphorylation of AMPK in skeletal muscle and liver of wild-type mice. However, Adipor1−/− Adipor2−/− double-knockout mice are not affected.

In the D-galactosamine-induced liver injury mice model, AdipoRon alleviates D-GalN induced hepatotoxicity in mice. And it prevents hepatic architecture distortion against D-GalN challenge. Notably, the hepatoprotective potential of AdipoRon is particularly evident in higher dosages (0.1 and 0.5 mg/kg).

In APN-deficient mice, AdipoRon (50 mg/kg, p.o.) administration reduces enhanced-cardiomyocyte apoptosis in APN-deficient mice. The antiapoptotic effect of AdipoRon is attenuated but not lost in AMPK-DN mice.

In conclusion, As an orally active adiponectin receptor (AdipoR) agonist, AdipoRon plays its role in vitro and in vivo.

[1]. Okada-Iwabu M, et al.Nature. 2013 Nov 28;503(7477):493-9.

[2]. Wang Y, et al. Eur J Pharm Sci. 2016 Aug 9;93:123-131.