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AIM: Liraglutide treatment is associated with gallbladder-related disorders and has been shown to delay postprandial gallbladder refilling. The gut hormones cholecystokinin (CCK), fibroblast growth factor 19 (FGF19) and glucagon-like peptide 2 (GLP-2), are known to regulate gallbladder motility and may be implicated in gallbladder-related disorders associated with liraglutide treatment.MATERIALS AND METHODS: In a double-blind, 12-week trial, 52 participants [50% male, age 47.6 ± 10.0 years, body mass index 32.6 ± 3.4 kg/m 2 (mean ± standard deviation)] with obesity were randomized 1:1 to once-daily subcutaneous liraglutide (escalated from 0.6 mg to 3.0 mg once-daily) or placebo. During liquid meal tests performed at baseline, after the first dose and following 12 weeks of treatment, we evaluated postprandial gallbladder dynamics and plasma responses of CCK, FGF19 and GLP-2. RESULTS: Liraglutide reduced postprandial FGF19 after the first dose [area under the curve (AUC) 0-240 min 24.8 vs. 48.0 min × ng/ml, treatment ratio (TR) (95% confidence interval) 0.52 (0.39; 0.69)] and following 12 weeks of treatment [AUC 0-240 min 33.7 vs. 48.5 ng/ml × min, TR 0.69 (0.52; 0.93)]. Liraglutide also reduced postprandial GLP-2 responses (AUC 0-240 min 3650 vs. 4894 min × pmol/L, TR 0.75 (0.62; 0.90)] following the first dose as well as after 12 weeks [AUC 0-240 min 3760 vs. 4882 min × pmol/L, TR 0.77 (0.60; 0.99)]. Liraglutide increased postprandial responses of CCK after the first dose [AUC 0-240 min 762 vs. 670 min × pmol/L; TR 1.14 (0.97; 1.33)] and following 12 weeks of treatment [AUC 0-240 min 873 vs. 628 min × pmol/L; TR 1.39 (1.12; 1.73)]. CONCLUSION: Compared with placebo, treatment with liraglutide decreased postprandial FGF19 and GLP-2 concentrations and increased postprandial CCK concentrations, which may explain the delayed postprandial gallbladder refilling observed in individuals with obesity treated with liraglutide.

Fibroblast growth factor 21 (FGF21) is a liver-derived hormone with pleiotropic metabolic effects. Its production is induced by various dietary imbalances in mice (including low-protein and ketogenic diets, fructose feeding and ethanol), hinting that it might influence food preference given the role of the liver in maintaining homeostatic levels of circulating nutrients. In 2016, it was shown that FGF21 selectively inhibits consumption of sugars and the primary product of their fermentation, ethanol, but not intake of fat, protein or complex carbohydrates. Since then, studies have sought to unravel this selectivity, its physiological purpose and translational relevance, as well as delineate the neural mechanisms involved. Initially found to impact ingestive behaviours in mice and non-human primates, FGF21 is also induced in humans by sugars and, far more dramatically, by acute alcohol intake. Genetic studies have revealed that patterns of weekly candy and alcohol consumption are associated with genetic variants in FGF21 and its co-receptor β-klotho (KLB), suggesting that liking for sugar, and fermented sugar, may be influenced by natural variation in FGF21 signal strength in humans. Herein, we discuss our nascent understanding of FGF21 as a selective negative regulator of sugar and alcohol appetite as well as reasons why such a peculiar system may have evolved in mammals. Uncovering the regulatory network governing sugar, and fermented sugar, intake could provide new opportunities to improve dietary choices in a population suffering from Western diet-induced diseases fuelled in part by a runaway sweet - and alcohol - tooth.