Stimulatory Effect of Allantoin on Imidazoline I1 Receptors in Animal and Cell Line

Abstract

Allantoin is known as the agonist of imidazoline receptor, especially the I₂ subtype. Effect of allantoin on imidazoline I₁ receptor (I₁R) relating to reduction of blood pressure and its merit in steatosis are still obscure. Also, farnesoid X receptor (FXR) plays an important role in lipid homeostasis related to I₁R activation. Thus, we administered allantoin into high fat diet (HFD)-fed mice showing hypertriglyceridemia and hypercholesterolemia. Allantoin significantly improved hyperlipidemia in HFD mice after 4 weeks of administration. Pretreatment with efaroxan, at a dose sufficient to inhibit I₁R activation, attenuated the action of allantoin. In addition, in cultured HepG2 cells, allantoin increased the expression of farnesoid X receptor (FXR). The allantoin-induced FXR expression was blocked by efaroxan. Similar changes were observed in the expressions of FXR-targeted genes. Otherwise, allantoin also lowered systolic blood pressure (SBP) in HFD mice that can be blocked by efaroxan. Taken together, allantoin has an ability to activate I₁R for improvement of metabolic disorders.

Decrease of Obesity by Allantoin via Imidazoline I1-Receptor Activation in High Fat Diet-Fed Mice

“…In the present study, allantoin effectively decreased eWAT cell size (Figure 2) and weight (Table 1) via the activation of I 1 R. This action of allantoin on eWAT is effective at a dose similar to the dose required to improve hepatic steatosis in HFD-fed mice [16]. Allantoin can thus be considered to affect lipid homeostasis via the activation of I 1 R [16]. …”

“…I 1 R is located in mainly the rostroventrolateral medulla of the brain stem, and it has also been identified in the hypothalamus [30, 31]. The activation of I 1 R has been reported to improve hypertension and hyperlipidemia [16]. Additionally, I 1 R activation was shown to attenuate hyperphagia in STZ-induced diabetic mice by lowering the hypothalamic NPY level [17], similar to the mechanism observed in Zucker rats [32].…”

“…Previous studies demonstrated that appetite was reduced by an increase in blood pressure [33, 34]. However, allantoin decreases appetite at a dose that is sufficient to lower blood pressure [16]. Thus, the change in blood pressure does not seem to be related to the change in feeding behavior caused by allantoin.…”

“…Recently, some herbs from the Dioscoreaceae have been shown to improve the symptoms of metabolic diseases via antihyperlipidemic and antioxidative effects [14, 15]. Allantoin has been shown to activate the imidazoline I 1 -receptor (I 1 R) in animal models and cell lines [16]. In addition, allantoin attenuates hyperlipidemia and improves hepatic steatosis via the activation of I 1 R to regulate farnesoid X receptor (FXR), demonstrating that I 1 R is involved in lipid homeostasis [16].…”

“…Allantoin has been shown to activate the imidazoline I 1 -receptor (I 1 R) in animal models and cell lines [16]. In addition, allantoin attenuates hyperlipidemia and improves hepatic steatosis via the activation of I 1 R to regulate farnesoid X receptor (FXR), demonstrating that I 1 R is involved in lipid homeostasis [16]. However, the effects of allantoin on obesity remain obscure.…”