Butyrylcholinesterase gene transfer in obese mice prevents postdieting body weight rebound by suppressing ghrelin signaling

Abstract

The worldwide prevalence of obesity is increasing at an alarming rate but treatment options remain limited. Despite initial success, weight loss by calorie restriction (CR) often fails because of rebound weight gain. Postdieting hyperphagia along with altered hypothalamic neuro-architecture appears to be one direct cause of this undesirable outcome. In response to calorie deficiency the circulating levels of the appetite-promoting hormone, acyl-ghrelin, rise sharply. We hypothesize that proper modulation of acyl-ghrelin and its receptor's sensitivity will favorably impact energy intake and reprogram the body weight set point. Here we applied viral gene transfer of the acylghrelin hydrolyzing enzyme, butyrylcholinesterase (BChE), in a mouse model of diet-induced obesity. Our results confirmed that BChE overexpression decreased circulating acyl-ghrelin levels, suppressed CRprovoked ghrelin signaling, and restored central ghrelin sensitivity. In addition to maintaining healthy body weights, BChE treated mice had modest postdieting food intake and showed normal glucose homeostasis. Spontaneous activity and energy expenditure did not differ significantly between treated and untreated mice after body weight rebound, suggesting that BChE gene transfer did not alter energy expenditure in the long term. These findings indicate that combining BChE treatment with CR could be an effective approach in treating human obesity and aiding lifelong weight management.butyrylcholinesterase | ghrelin | diet-induced obesity | food intake | body weight rebound

LEAP2 changes with body mass and food intake in humans and mice

“…Interestingly, the human studies demonstrated higher fasted plasma LEAP2 only in those with BMI greater than 35 to 40 kg/m 2 , suggesting that milder degrees of obesity may not be associated with the "protective" elevations of LEAP2 and might benefit from therapies that would boost plasma LEAP2 (for instance, to curb appetite and reduce food reward). Similarly, therapies that increase plasma LEAP2 might also be beneficial particularly in individuals with obesity who have achieved weight loss, so as to counteract the naturally occurring falls in LEAP2 that otherwise may contribute to rebound weight gain, coincident with increases in plasma ghrelin (69,70). Such LEAP2-based therapies could be impactful after lifestyle modification or gastric-banding surgery, in which there is no coincident beneficial increase in satiety gut hormones, such as peptide YY (PYY) and glucagon-like peptide 1, or decrease in acylghrelin, unlike after RYGB and/or VSG surgery.…”

Effects of Rikkunshito treatment on renal fibrosis/inflammation and body weight reduction in a unilateral ureteral obstruction model in mice

“…All quantitative data are expressed as the mean ± SEM. Differences in body weight among the four groups over time were analysed by two-way repeated measures ANOVA with Bonferroni's post-test as previously described [23][24][25][26] . Differences between sham and UUO mice for each diet and between CTL and RKT within each surgery were tested by two-factor ANOVA with Bonferroni's post-test.…”

Treating Cocaine Addiction, Obesity, and Emotional Disorders by Viral Gene Transfer of Butyrylcholinesterase

“…The key question was, would it blunt the intense food cravings that drive seemingly inevitable rebound weight gain after a long supervised diet has returned an obese person to healthy body weight? Addressing this issue in a recent publication ( Chen et al, 2017 ), we assigned C57BL mice to two treatment groups for gene transfer with AAV8 viral vector. The vector for Group 1 encoded BChE while that for Group 2, controls, encoded the irrelevant protein, firefly luciferase.…”

“…(a) Significant with respect to chow group; (b) significant with respect to HFD group; (c) significant with respect to CR + AAV-Luc group. Significance was set at P < 0.05 by two-way repeated-measures ANOVA Chen et al (2017) .…”