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Bile Acid Composition Regulates GPR119-Dependent Intestinal Lipid

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Bile Acid Composition Regulates GPR119-Dependent Intestinal Lipid Nutrition ORIGINAL RESEARCH Bile acid composition regulates GPR119- dependent Gut: first published as 10.1136/gutjnl-2019-319693 on 28 February 2020. Downloaded from intestinal lipid sensing and food intake regulation in mice Sei Higuchi,1 Tiara Rinjani Ahmad,1 Donovan A Argueta,2 Pedro A Perez,2 Chen Zhao,3 Gary J Schwartz,4 Nicholas DiPatrizio,2 Rebecca Haeusler 1 ► Additional material is ABSTRact published online only. To view Objectives Lipid mediators in the GI tract regulate Significance of this study please visit the journal online satiation and satiety. Bile acids (BAs) regulate the (http:// dx. doi. org/ 10. 1136/ What is already known on this subject? gutjnl- 2019- 319693). absorption and metabolism of dietary lipid in the ► Hydrolysed intestinal lipids induce satiety and 1 intestine, but their effects on lipid- regulated satiation Pathology and Cell Biology, satiation. Columbia University Medical and satiety are completely unknown. Investigating this The subset of bile acids that are Center, New York, New York, is challenging because introducing excessive BAs or ► USA eliminating BAs strongly impacts GI functions. We used 12α-hydroxylated are synthesised at a higher 2Division of Biomedical a mouse model (Cyp8b1–/– mice) with normal total rate in obesity and insulin resistance. Sciences, University of California BA levels, but alterations in the composition of the BA ► Deleting Cyp8b1, the enzyme required to Riverside, Riverside, California, produce 12α-hydroxylated bile acids, impairs USA pool that impact multiple aspects of intestinal lipid 3Institute of Human Nutrition, metabolism. We tested two hypotheses: BAs affect food intestinal lipid absorption in mice. Columbia University, New York, intake by (1) regulating production of the bioactive lipid What are the new findings? New York, USA oleoylethanolamide (OEA), which enhances satiety; or (2) 4Departments of Medicine and ► Lowering 12α-hydroxylated bile acids in mice Neuroscience, Yeshiva University regulating the quantity and localisation of hydrolysed fat slows lipid hydrolysis and allows lipid access Albert Einstein College of in small intestine, which controls gastric emptying and to the lower intestine, which slows gastric Medicine, Bronx, New York, USA satiation. emptying and reduces food intake. Design We evaluated OEA levels, gastric emptying –/– ► The fat receptor GPR119 mediates this lipid- Correspondence to and food intake in wild- type and Cyp8b1 mice. We sensing pathway. Dr Rebecca Haeusler, Pathology assessed the role of the fat receptor GPR119 in these and Cell Biology, Columbia ► The effects of this pathway on gastric emptying effects using Gpr119–/– mice. University Medical Center, New –/– require intact signalling through the gut http://gut.bmj.com/ York, NY 10032, USA; Results Cyp8b1 mice on a chow diet showed mild hormones GLP-1 and PYY. rah2130@ columbia. edu hypophagia. Jejunal OEA production was blunted in Cyp8b1–/– mice, thus these data do not support a role How might it impact on clinical practice in the Received 21 August 2019 for this pathway in the hypophagia of Cyp8b1–/– mice. foreseeable future? Revised 21 January 2020 Accepted 6 February 2020 On the other hand, Cyp8b1 deficiency decreased gastric ► Cyp8b1 inhibition is a potential target for obesity emptying, and this was dependent on dietary fat. and diabetes treatment. GPR119 deficiency normalised the gastric emptying, on October 6, 2021 by guest. Protected copyright. gut hormone levels, food intake and body weight of Cyp8b1–/– mice. Conclusion BAs regulate gastric emptying and mechanism is initiated by the presence of dietary satiation by determining fat- dependent GPR119 activity fat in the intestine, particularly the lower intestine, in distal intestine. which slows gastric emptying. This results in gastric distention, enhances the perception of fullness and results in satiation—defined as a decrease in meal size.5 This satiation is expected to be mediated INTRODUCTION partly by enteroendocrine cells of the lower intes- Feeding behaviour is governed in the brain and in tine, which secrete gut hormones such as GLP-1 the GI tract. Infusion of fat directly into duodenum and PYY in response to the products of dietary © Author(s) (or their potently decreases food intake,1–4 indicating that fat triglyceride hydrolysis: free fatty acids (FFA) and employer(s)) 2020. Re- use sensing in the GI tract is a vital element to induce 2- monoacylglycerol (2- MAG). Hormone secre- permitted under CC BY-­NC. No hypophagia. There are at least two mechanisms by tion in response to FFA and 2- MAG is expected commercial re- use. See rights and permissions. Published which intestinal fat suppresses food intake. One is to be carried out by G protein–coupled receptors 7–9 by BMJ. initiated within enterocytes of the jejunum, where (GPCRs). GPR119 is one candidate receptor, dietary fat is converted into fatty acid ethanol- and it can be activated by 2-MA G.7 8 Thus, intes- To cite: Higuchi S, Ahmad TR, amides (FAEs), such as oleoylethanolamide (OEA). tinal lipids derived from dietary fat have the poten- Argueta DA, et al. Gut Epub ahead of print: [please Jejunal OEA is a bioactive signalling lipid that tial to induce at least two pathways—one in the include Day Month Year]. induces satiety—defined as an increase in the time jejunal intestine via OEA- PPARα and one in the doi:10.1136/ interval between meals—via PPARα activation and lower intestine via 2- MAG- GPR119—to promote gutjnl-2019-319693 the vagally mediated gut–brain axis.1 4–6 A second both satiety and satiation. Existing experimental Higuchi S, et al. Gut 2020;0:1–9. doi:10.1136/gutjnl-2019-319693 1 Nutrition paradigms cannot easily distinguish which of these pathways is Cyp8b1–/– mice with GPR119–/– mice to obtain double knockout dominant in the regulation of total food intake. mice, and used littermate male mice between 8 and 15 weeks Bile acids (BAs) emulsify dietary lipid, which allows it to be of age for experiments. Mice were fed a normal chow diet (3.4 Gut: first published as 10.1136/gutjnl-2019-319693 on 28 February 2020. Downloaded from efficiently hydrolysed and absorbed in the proximal intestine. kcal/g, Purina 5053, 24.7% kcal from protein, 62.1% carbo- Data from mice demonstrate that among endogenous BA species, hydrate and 13.2% fat), a fat-free diet (3.3 kcal/g, Envigo TD this lipid absorption function is most effectively carried out 03314, 24.2% kcal from protein and 75.8% from carbohydrate) by cholic acid (CA).10–13 We reasoned that the composition of or a high-fat diet (5.21 kcal/g, Research Diets D12492, 20.0% endogenous BAs determines whether fat is absorbed efficiently kcal from protein, 20.0% carbohydrate and 60.0% fat). Mice in the upper small intestine or whether unabsorbed lipid species, were provided with the diet and water ad libitum and main- such as 2- MAG, enter the distal intestine where they may acti- tained on a 12- hour light/dark cycle, set with lights on at 7:00. vate enteroendocrine cell–induced satiation. BAs also have an For food intake measurements, mice were individually housed, allosteric function in which they can bind within the substrate and the food dispenser was located inside the cage. binding pocket of, and stabilise the activity of, the enzyme N- Detailed methods can be found in supplementary materials acyl phosphatidylethanolamine phospholipase D (NAPE- PLD), and methods. which produces appetite- regulating lipid mediators such as OEA and arachidonolyethanolamide (AEA).14 15 This stabilising func- tion is most effectively carried out by deoxycholic acid (DCA). Statistics Thus, BAs may contribute to intestinal lipid sensing in multiple Results are presented as mean±SEM. Data were analysed by ways, but their roles are incompletely defined. one-way and two-way ANOVA with Tukey’s multiple compar- Others and we have previously reported that mice lacking the isons test or Student’s t- test. 12α-hydroxylase Cyp8b1 have no decrease in the total levels of BAs, but an altered BA composition, with a lack of the 12α-hy- 12 13 droxylated BAs CA and DCA, and their conjugated forms. RESULTS –/– These mice also have impaired absorption of dietary cholesterol Reduced food intake induces low body weight of Cyp8b1 and triglycerides.10–13 Because Cyp8b1–/– mice have normal total mice levels of BAs, this impairment in lipid absorption is due to the Cyp8b1–/– mice maintained on standard chow diet showed a lack of 12α-hydroxylated (12- OH) BAs and the inefficiency ~10% reduction in body weight compared with wild-type (WT) of the remaining non-12- OH BAs to promote lipid absorp- mice, which was attributable to small but statistically significant tion. 12- OH BAs comprise CA, DCA and their conjugates; decreases in both adiposity and lean mass (figure 1A–F).10 11 13 non-12- OH BAs include muricholic acids (MCAs), chenodeoxy- Ad libitum chow intake of Cyp8b1–/– mice was slightly decreased cholic acid (CDCA) and their conjugates. The consequence of (figure 1G) relative to WT controls. Indirect calorimetry exper- this impairment is that a small amount of dietary fat travels the iments showed no differences in respiratory exchange ratio, full length of the GI tract, ultimately appearing in the faeces. We oxygen consumption, heat production or activity between geno- reasoned that Cyp8b1–/– mice may be a new tool to (1) dissect types (online supplementary figure 1A–D). To test whether this the role(s) of BAs on intestinal lipid sensing and (2) investigate level of food intake was sufficient to induce the low body weight the relative contributions of different intestinal lipid sensing of Cyp8b1–/– mice, we performed a pair- feeding experiment. http://gut.bmj.com/ pathways on food intake. Body weights of pairfed WT mice decreased to the level of the Cyp8b1–/– mice (figure 1H). Taken together, these data support MatERIALS AND METHODS the suggestion that reduced food intake contributed to the lower Animal experiments body weight of Cyp8b1–/– mice.
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