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

Abstract

ObjectivesLipid 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.DesignWe 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.ResultsCyp8b1–/– 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.ConclusionBAs regulate gastric emptying and satiation by determining fat-dependent GPR119 activity in distal intestine.

Anti-Adipogenic Effect of Theabrownin Is Mediated by Bile Acid Alternative Synthesis via Gut Microbiota Remodeling

“…Loss of Cyp8b1 resulted in lower amounts of 12OH-BAs, including CA, a highly efficient BA in mixed micelle formation for dietary fat and cholesterol absorption [ 21 , 22 ]. Thus, lack of CA will result in slowing lipid hydrolysis and allowing lipid access to the lower intestine, which slows gastric emptying and reduces food intake via the gut hormones, GLP1 and PYY mediated GPR-119 signaling pathway [ 23 ].…”

Association between duodenal bile salts and gastric emptying in patients with functional dyspepsia

“…We read with interest the study by Higuchi et al, which identified mechanisms of increased satiation in Cyp8b1−/− mice via slowed gastric empting. 1 Following data showing that deleting Cyp8b1, which is required to produce 12α-hydroxylated bile acids, impaired intestinal lipid absorption in mice, the authors convincingly demonstrated that lowering 12α-hydroxylated bile acids slowed gastric emptying in Cyp8b1−/− mice. 1 Duodenal lipid infusion affects gastric function, and duodenal hypersensitivity to lipids has been studied in GI disorders with gastric dysmotility, such as functional dyspepsia (FD).…”

“…1 Following data showing that deleting Cyp8b1, which is required to produce 12α-hydroxylated bile acids, impaired intestinal lipid absorption in mice, the authors convincingly demonstrated that lowering 12α-hydroxylated bile acids slowed gastric emptying in Cyp8b1−/− mice. 1 Duodenal lipid infusion affects gastric function, and duodenal hypersensitivity to lipids has been studied in GI disorders with gastric dysmotility, such as functional dyspepsia (FD). 2 FD is defined by upper GI symptoms originating from the gastroduodenal region with no structural disease on routine investigation.…”

“…10 Interestingly, treatment with 12-hydroxylated bile acids normalised the slow gastric emptying in Cyp8b1−/− mice and caused faster emptying compared with non-12hydroxylated bile acids in healthy mice. 1 Although confirmation is needed, it is possible that the effect differs in patients with FD with duodenal and/or gastric hypersensitivity. 2 4 6 In conclusion, we showed that lower concentrations of 12α-hydroxylated bile salts were associated with slower gastric emptying in patients with FD, similar to Cyp8b1−/− mice.…”

Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease

“…In light of the effects of bile acids on appetite regulation, particularly via the secretion of gastrointestinal hormones, it is intuitively likely that modulating bile acid signaling affects energy balance. Genetic ablation of the bile acid synthesis enzyme CYP8B1, leading to a deficiency of 12α-hydroxylated bile acids (e.g., CA), has been shown to be associated with reduced energy intake and subsequent weight gain in mice fed a fat enriched diet [ 48 , 49 ]. However, these effects appeared to be secondary to impaired fat hydrolysis and the increased exposure of unabsorbed fat to the distal gut, as in these mice, there was an increase in energy intake when fed a fat-free diet [ 49 ].…”