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

PLoS One. 2015 Oct 27;10(10):e0141327. doi: 10.1371/journal.pone.0141327. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists / administration & dosage
  • Adrenergic alpha-2 Receptor Antagonists / administration & dosage
  • Animals
  • Appetite Depressants / administration & dosage
  • Appetite Depressants / adverse effects
  • Body Weight / drug effects
  • Diet, High-Fat
  • Guanfacine / administration & dosage*
  • Guanfacine / adverse effects
  • Heart Rate / drug effects
  • Humans
  • Ligands
  • Obesity / drug therapy*
  • Obesity / genetics
  • Obesity / pathology
  • Rats
  • Receptors, Adrenergic, alpha-2 / genetics
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • United States
  • Yohimbine / administration & dosage*
  • Yohimbine / adverse effects

Substances

  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-2 Receptor Antagonists
  • Appetite Depressants
  • Ligands
  • Receptors, Adrenergic, alpha-2
  • Yohimbine
  • Guanfacine

Grants and funding

The studies described in the above paper were financially supported by the National Science Centre in Poland within the grant entitled “Partial agonists of alpha-2 adrenoceptors as a new perspective of the effective and safe in reducing body weight and obesity” (decision no. DEC-2011/03/B/NZ7/00635), http://www.ncn.gov.pl, MD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.