A randomized crossover trial assessing the effects of acute exercise on appetite, circulating ghrelin concentrations, and butyrylcholinesterase activity in normal-weight males with variants of the obesity-linked FTO rs9939609 polymorphism

Abstract

Background The fat mass and obesity-associated gene (FTO) rs9939609 A-allele is associated with higher acyl-ghrelin (AG) concentrations, higher energy intake, and obesity, although exercise may mitigate rs9939609 A-allele–linked obesity risk. Butyrylcholinesterase (BChE) hydrolyzes AG to des-acyl-ghrelin (DAG), potentially decreasing appetite. However, the effects of the FTO rs9939609 genotype and exercise on BChE activity, AG, DAG, and energy intake are unknown. Objective We hypothesized that individuals homozygous for the obesity-risk A-allele (AAs) would exhibit higher postprandial AG and energy intake than individuals homozygous for the low obesity-risk T-allele (TTs), but that exercise would increase BChE activity and diminish these differences. Methods Twelve AA and 12 TT normal-weight males completed a control (8 h rest) and an exercise (1 h of exercise at 70% peak oxygen uptake, 7 h rest) trial in a randomized crossover design. A fixed meal was consumed at 1.5 h and an ad libitum buffet meal at 6.5 h. Appetite, appetite-related hormones, BChE activity, and energy intake were assessed. Results AAs displayed lower baseline BChE activity, higher baseline AG:DAG ratio, attenuated AG suppression after a fixed meal, and higher ad libitum energy intake compared with TTs [effect sizes (ESs) ≥ 0.72, P ≤ 0.049]. Exercise increased Δ BChE activity in both genotypes (ESs = 0.37, P = 0.004); however, exercise lowered AG and the AG:DAG ratio to a greater extent in AAs (P ≤ 0.023), offsetting the higher AG profile observed in AAs during the control trial (ESs ≥ 1.25, P ≤ 0.048). Exercise did not elevate energy intake in either genotype (P = 0.282). Conclusions Exercise increases BChE activity, suppresses AG and the AG:DAG ratio, and corrects the higher AG profile observed in obesity-risk AA individuals. These findings suggest that exercise or other methods targeting BChE activity may offer a preventative and/or therapeutic strategy for AA individuals. This trial was registered at clinicaltrials.gov as NCT03025347.

Similarities in Metabolic Flexibility and Hunger Hormone Ghrelin Exist between FTO Gene Variants in Response to an Acute Dietary Challenge

“…However, similar to our study, they found no difference in fasting concentrations of AG between genotypes, but when presented as a ratio of AG/des-acyl-ghrelin (DAG), AA genotype demonstrated higher levels compared to TT [13]. Interestingly, the Dorling et al [13] study also observed lower fasting butyrylcholinesterase (BChE) activity in carriers of AA compared to TT, which may offer a potential explanation for the reported higher AG:DAG ratio and energy intake between genotypes. BChE activity increases AG hydrolysis in plasma, leading to greater DAG and a lower AG:DAG ratio, which has been linked to lower energy consumption and lower adiposity in mice [12].…”

“…In contrast, Karra et al [11] observed elevated basal ghrelin mRNA expression in peripheral blood cells and reduced suppression of circulating ghrelin in FTO risk A-allele carriers within a subset of 20 individuals. In a comparable cohort, Dorling and colleagues also found an attenuated AG suppression after a fixed meal, which coincided with higher ad libitum energy intake compared with TT [13]. However, similar to our study, they found no difference in fasting concentrations of AG between genotypes, but when presented as a ratio of AG/des-acyl-ghrelin (DAG), AA genotype demonstrated higher levels compared to TT [13].…”

“…In a comparable cohort, Dorling and colleagues also found an attenuated AG suppression after a fixed meal, which coincided with higher ad libitum energy intake compared with TT [13]. However, similar to our study, they found no difference in fasting concentrations of AG between genotypes, but when presented as a ratio of AG/des-acyl-ghrelin (DAG), AA genotype demonstrated higher levels compared to TT [13]. Interestingly, the Dorling et al [13] study also observed lower fasting butyrylcholinesterase (BChE) activity in carriers of AA compared to TT, which may offer a potential explanation for the reported higher AG:DAG ratio and energy intake between genotypes.…”

“…Increased expression and a subsequent rise in circulating acyl-ghrelin (AG) levels has been linked to greater food intake and a preference for energy-dense foods [12]. Recently, higher postprandial AG concentrations, which coincided with higher postprandial appetite and ad libitum energy intake, have also been evident in FTO rs9939609 risk A-allele compared to those homozygous to TT [13]. While the evidence suggests that FTO rs9939609 genotype impacts circulating AG levels [11], impaired central nervous system satiety processing could also be a factor contributing to reduced satiety and increased food intake [14].…”

The association between FTO genotype with macronutrients and calorie intake in overweight adults

“…The cause of this discrepancy between the studies remained unclear. However, the relationship between FTO genotype and dietary intake seems to be very complex and many factors may have a role in this association such as the obesity [ 29 ], level of physical activity [ 19 ], serum leptin [ 30 ], and other dietary components [ 29 , 30 ]. However, only overweight subjects were included because of the possible effect of BMI on the association between FTO genotype and dietary intake.…”