Physiological roles for butyrylcholinesterase: A BChE-ghrelin axis

Abstract

Butyrylcholinesterase (BChE) has long been regarded as an "orphan enzyme" with no specific physiological role other than to metabolize exogenous bioactive esters in the diet or in medicines. Human beings with genetic mutations that eliminate all BChE activity appear completely normal, and BChE-knockout mice have been described as "lacking a phenotype" except for faster weight gain on high-fat diets. However, our recent studies with viral gene transfer of BChE in mice reveal that BChE hydrolyzes the so-called "hunger hormone," ghrelin, at a rate which strongly affects the circulating levels of this peptide hormone. This action has important consequences for weight gain and fat metabolism. Surprisingly, it also impacts emotional behaviors such as aggression. Overexpression of BChE leads to low ghrelin levels in the blood stream and reduces aggression and social stress in mice. Under certain circumstances these combined effects contribute to increased life-span in group-housed animals. These findings may generalize to humans, as recent clinical studies by multiple investigators indicate that, among patients with severe cardiovascular disease, longevity correlates with increasing levels of plasma BChE activity.

Keywords: Aggression; Butyrylcholinesterase; Ghrelin; Growth hormone secretagogue receptor; Obesity.

Fig 1

Unpublished findings from long-term daily observations of group-housed male mice (32 pooled controls and 30 mice transduced at six weeks with adeno-associated virus (AAV) or helper dependent virus vector encoding mutated mouse BChE, “mBChE mut”). Plasma BChE levels in the vectors treated group were ~100-fold above normal and were sustained for the following 2 years. Initially, mice were housed 5 per cage, until signs of fighting arose (4 to 5 months), when they moved to single cage housing. The varied housing conditions prevent a definitive judgment of true lifespan although ANOVA showed a significant main effect of treatment (controls vs pooled vector-treated groups): F_1,60 = 13.64, P < 0.001. No post-hoc testing was performed.

Fig 2

Bite scores in confrontations between a resident male mouse and a male intruder [10]. A. 3-month Balb/c with AAV-luciferase vector (n = 18) versus mBChE mutant vector-treated (n = 7); AAV-CocH-6 ΔT treated mice (n = 14). B. AAV-luciferase treated 3-month C57BL/6 wild type (n = 9) versus same age C57BL/6 treated simultaneously with AAV vectors encoding cDNA for ghrelin and GOAT (n = 6); and same-age mice treated triply, with vectors for ghrelin, GOAT, and mBChE mutant (n = 9). *p < 0.05; *** p < 0.001; n.s., not significant.

Fig 3

The BChE-ghrelin axis. Ghrelin is predominantly produced by the stomach and secreted into the blood stream. It crosses the blood brain barrier and affects growth hormone release from the pituitary gland, impacting appetite, stress responses, insulin sensitivity and even life span. Ghrelin is also produced, stored, and released in specific brain loci. In the hypothalamus it activates circuits that regulate hunger and body temperature. In the amygdala it affects emotions including fear, anxiety, and aggression. BChE in liver, plasma, and brain can hydrolyze ghrelin and transform it into its inactive desacyl form. This regulatory pathway appears to be physiologically important.