Bile acid composition regulates GPR119-dependent intestinal lipid sensing and food intake regulation in mice

Objectives Lipid mediators in the GI tract regulate satiation and satiety. Bile acids (BAs) regulate the absorption and metabolism of dietary lipid in the intestine, but their effects on lipid-regulated satiation and satiety are completely unknown. Investigating this is challenging because introducing excessive BAs or eliminating BAs strongly impacts GI functions. We used a mouse model (Cyp8b1(-/-) mice) with normal total BA levels, but alterations in the composition of the BA pool that impact multiple aspects of intestinal lipid metabolism. We tested two hypotheses: BAs affect food intake by (1) regulating production of the bioactive lipid oleoylethanolamide (OEA), which enhances satiety; or (2) regulating the quantity and localisation of hydrolysed fat in small intestine, which controls gastric emptying and satiation. Design We evaluated OEA levels, gastric emptying and food intake in wild-type and Cyp8b1(-/-) mice. We assessed the role of the fat receptor GPR119 in these effects using Gpr119(-/-) mice. Results Cyp8b1(-/-) mice on a chow diet showed mild hypophagia. Jejunal OEA production was blunted in Cyp8b1(-/-) mice, thus these data do not support a role for this pathway in the hypophagia of Cyp8b1(-/-) mice. On the other hand, Cyp8b1 deficiency decreased gastric emptying, and this was dependent on dietary fat. GPR119 deficiency normalised the gastric emptying, gut hormone levels, food intake and body weight of Cyp8b1(-/-) mice. Conclusion BAs regulate gastric emptying and satiation by determining fat-dependent GPR119 activity in distal intestine.