Attenuation of satiety gut hormones increases appetitive behavior after curative esophagectomy for esophageal cancer

Abstract

Background Reduced appetite and weight loss are common after esophagectomy (ES), and this cohort demonstrates an exaggerated postprandial satiety gut hormone response. Satiety gut hormones modulate food reward, resulting in reduced energy intake. Objectives This study aimed to determine the effect of satiety gut hormone modulation by measuring the effect of the somatostatin analog octreotide on appetitive behavior among patients after ES. Methods In this randomized, double-blind, placebo-controlled crossover study, patients ≥1 y after ES and matched controls received either 1 mL 0.9% saline or 1 mL (100 μg) octreotide subcutaneously before completing a progressive ratio task. A measure of appetitive behavior, this task requires subjects to undertake progressively increasing amounts of work to obtain a sweet-fat reinforcer; the final completed increment (breakpoint) represents reinforcer reward value. Separate cohorts were studied in the fasted or 1-h postprandial states. Results Thirty-six subjects (ES, n = 18; matched controls, n = 18) were studied. The ES subjects were 2.5 ± 0.3 y postoperation and had a weight loss of 14.6% ± 2.6% and elevated postprandial glucagon-like peptide 1 compared with controls (49.2 ± 13.4 compared with 20.2 ± 2.3 pM; P = 0.04). Octreotide did not alter the breakpoint among ES or control subjects when tested in a fasting condition (ES: 980 ± 371 compared with 1700 ± 584 clicks; P = 0.16; controls: 1056 ± 274 compared with 1124 ± 273 clicks; P = 0.81). When tested 1 h postprandially, octreotide was associated with an increased breakpoint compared with placebo among ES subjects (322 ± 143 compared with 246 ± 149 clicks; P = 0.04) but not controls (248 ± 119 compared with 247 ± 120 clicks; P = 0.97). Conclusions Attenuation of the exaggerated postprandial satiety gut hormone response is associated with increased appetitive behavior toward a sweet-fat stimulus among patients post-ES. Suppression of satiety gut hormones may be a novel target to increase appetite, food intake, and body weight among patients after ES. This study was registered at clinicaltrials.gov as NCT02381249.

Ghrelin and Glucagon-Like Peptide-1: A Gut-Brain Axis Battle for Food Reward

“…In fact, indirect inhibition of GLP-1 secretion via sc injection of octreotide, a somatostatin analog, enhances computer mouse clicks for chocolate rewards in individuals who underwent RYGB surgery but not in obese nonoperated controls, suggesting that RYGB surgery influences the effects of GLP-1 signaling on food-motivated responses [99]. Similarly, patients who underwent esophagectomy for cancer present elevated postprandial levels of GLP-1 relative to healthy control subjects and also present an increase in computer mouse clicks for chocolate following sc injection of octreotide, whereas healthy controls do not [100]. Thus, the extent to which GLP-1 signaling dampens food motivation is influenced by chronic metabolic status.…”

A Pilot Study of Gut-Brain Signaling After Octreotide Therapy for Unintentional Weight Loss After Esophagectomy

“…This is important to bear in mind when interpreting these findings and could feasibly underlie the lack of a positive effect with regards to body weight and composition with treatment. This is particularly pertinent as the studies describing an impact of short-acting Octreotide did demonstrate significant GLP-1 attenuation (27,28). There was no clear precedent on which to base the dosing in this clinical context.…”

“…This was a pilot study with the principal aim to determine feasibility of the protocol and effect size of the outcomes. When planning the study we used the PRT breakpoint as primary outcome as our previous data demonstrated that the difference in the response of matched pairs to Octreotide is normally distributed and is 88 with standard deviation of 47 (28). Were these values used, with a A c c e p t e d M a n u s c r i p t significance level of 0.05 and 0.9 power, then 5 participants would be needed to detect a difference with Octreotide LAR treatment.…”

“…Octreotide also increased motivation to eat in the acute setting, inducing a stronger desire to obtain a sweet-fat stimulus. (28) Several aspects of gut-brain signaling, however, remain unexplored in this operative context. First, the association between gut hormone suppression therapy post-esophagectomy and anticipatory food reward on fMRI is unknown.…”

The Role of the Small Bowel in Unintentional Weight Loss after Treatment of Upper Gastrointestinal Cancers

“…The inhibition of the satiety gut hormone responses with a somatostatin analogue almost doubled ad libitum food intake [49]. Elliott et al showed that administration of octreotide in patients after esophagectomy led to attenuation of exaggerated postprandial satiety gut hormone responses which was associated with increased appetitive behavior toward a sweet-fat stimulus [71].…”