A Comparison of the Anorectic Effect and Safety of the Alpha2-Adrenoceptor Ligands Guanfacine and Yohimbine in Rats with Diet-Induced Obesity.

Magdalena Dudek,Marek Bednarski,Leszek Nowiński,Joanna Knutelska,Małgorzata Zygmunt,Monika Głuch-Lutwin,Karolina Pytka,Barbara Mordyl,Grzegorz Kazek,Jacek Sapa

doi:10.1371/journal.pone.0141327

Abstract

The search for drugs with anorectic activity, acting within the adrenergic system has attracted the interest of researchers. Partial α2-adrenoceptor agonists might offer the potential for effective and safe treatment of obesity. We compared the effectiveness and safety of α2-adrenoceptor ligands in reducing body mass. We also analyzed if antagonist and partial agonists of α2-adrenoceptor––yohimbine and guanfacine––act similarly, and determined which course of action is connected with anorectic activity. We tested intrinsic activity and effect on the lipolysis of these compounds in cell cultures, evaluated their effect on meal size, body weight in Wistar rats with high-fat diet-induced obesity, and determined their effect on blood pressure, heart rate, lipid profile, spontaneous locomotor activity, core temperature and glucose, as well as glycerol and cortisol levels. Both guanfacine and yohimbine showed anorectic activity. Guanfacine was much more effective than yohimbine. Both significantly reduced the amount of intraperitoneal adipose tissue and had a beneficial effect on lipid profiles. Decreased response of α2A-adrenoceptors and partial stimulation of α2B-receptors seem to be responsible for the anorectic action of guanfacine. The stimulation of α1-adrenoceptors by guanfacine is responsible for cardiovascular side effects but may also be linked with improved anorexic effect. α1-adrenoceptor blockade is connected with the side effects of yohimbine, but it is also associated with the improvement of lipid profiles. Guanfacine has been approved by the Food and Drug Administration (FDA) to treat hypertension and conduct disorder, but as it reduces body weight, it is worth examining its effectiveness and safety in models of obesity.

Highlights

Obesity is affecting an increasing number of individuals in the human population [1]
This study for the first time clearly indicates the effective anorectic action of guanfacine in obese rats, and shows that such an effect can be achieved by partial α2A/B-adrenoreceptor agonists
This is the first report that partial α2-adrenoreceptor agonists may possess body weight reducing activity in the model of obesity

Summary

Introduction

Obesity is affecting an increasing number of individuals in the human population [1]. Obese people more frequently suffer from cardiovascular diseases, diabetes, and diseases of the digestive system, and are at higher risk of developing cancer [3]. This shows the importance of conducting research leading to the discovery of a drug that will effectively reduce weight. The higher doses of this drug, which were used for weight reduction, affected α1-adrenoreceptors as well Since yohimbine at such doses can block both postsynaptic α1- and α2-adrenoceptors present in arterial vessels, there is a risk of a very significant drop in blood pressure

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