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Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods123

Increased colonic propionate reduces anticipatory reward responses in the human striatum to... Original Research Communications See corresponding editorial on page 1. Increased colonic propionate reduces anticipatory reward responses in 1–3 the human striatum to high-energy foods 4 4 4 5 8 8 Claire S Byrne, Edward S Chambers, Habeeb Alhabeeb, Navpreet Chhina, Douglas J Morrison, Tom Preston, 9 7 7 7 10 10 Catriona Tedford, Julie Fitzpatrick, Cherag Irani, Albert Busza, Isabel Garcia-Perez, Sofia Fountana, 10 5,6,11 4,11 Elaine Holmes, Anthony P Goldstone, * and Gary S Frost * 4 5 Nutrition and Dietetic Research Group, Division of Diabetes, Endocrinology and Metabolism, Faculty of Medicine, Computational, Cognitive and Clinical 6 7 Neuroimaging Laboratory and Centre for Neuropsychopharmacology, Division of Brain Sciences, and Clinical Imaging Facility, Imperial College London, Hammersmith Hospital, London, United Kingdom; Stable Isotope Biochemistry Laboratory, Scottish Universities Environmental Research Centre, University 9 10 of Glasgow, Glasgow, United Kingdom; School of Science, University of West Scotland, Hamilton, United Kingdom; and Department of Surgery and Cancer, Computational and Systems Medicine, Imperial College London, South Kensington Campus, London, United Kingdom ABSTRACT Keywords: propionate, striatum, reward, fMRI, appetite Background: Short-chain fatty acids (SCFAs), metabolites pro- duced through the microbial fermentation of nondigestible dietary INTRODUCTION components, have key roles in energy homeostasis. Animal research suggests that colon-derived SCFAs modulate feeding behavior via Peripheral signals communicate information about current energy central mechanisms. In humans, increased colonic production of the balance to the brain to maintain energy homeostasis (1). The hedonic SCFA propionate acutely reduces energy intake. However, evidence properties and constant availability of highly palatable energy-dense of an effect of colonic propionate on the human brain or reward- foods promote their overconsumption and weight gain, whereas based eating behavior is currently unavailable. hedonic and reward-based eating behaviors are in turn influenced by Objectives: We investigated the effect of increased colonic propi- peripheral homeostatic signals such as gut hormones (2–4). Hedonic onate production on brain anticipatory reward responses during food responses to food are thought to involve a network of corticolimbic picture evaluation. We hypothesized that elevated colonic propionate brain structures, and are modulated by emotional and cognitive would reduce both reward responses and ad libitum energy intake via factors, as well as sensory cues and anticipated reward. stimulation of anorexigenic gut hormone secretion. Design: In a randomized crossover design, 20 healthy nonobese men This article presents independent research funded by Imperial College (IC) completed a functional magnetic resonance imaging (fMRI) food picture London and supported by the National Institute for Health Research (NIHR) evaluation task after consumption of control inulin or inulin-propionate Clinical Research Facility and Biomedical Research Centre at IC Healthcare NHS Trust. The Section of Endocrinology and Investigative Medicine is ester, a unique dietary compound that selectively augments colonic pro- funded by grants from the Medical Research Council (MRC), Biotechnology pionate production. The blood oxygen level–dependent (BOLD) signal and Biological Sciences Research Council (BBSRC), and NIHR, an Integrative wasmeasuredinapriori brainregions involved in reward processing, Mammalian Biology Capacity Building Award, and an FP7-HEALTH-2009- including the caudate, nucleus accumbens, amygdala, anterior insula, and 241592 EuroCHIP grant, and is supported by the NIHR Biomedical Research orbitofrontal cortex (n = 18 had analyzable fMRI data). Centre Funding Scheme. GSF holds an NIHR Senior Investigator Award, CSB Results: Increasing colonic propionate production reduced BOLD signal and APG are funded by the United Kingdom MRC, and ESC is funded by the during food picture evaluation in the caudate and nucleus accumbens. In BBSRC. This is an open access article distributed under the CC-BY license the caudate, the reduction in BOLD signal was driven specifically by (http://creativecommons.org/licenses/by/3.0/). The views expressed are those of the authors and not necessarily those of a lowering of the response to high-energy food. These central effects IC, the NHS, the NIHR, or the Department of Health. were partnered with a decrease in subjective appeal of high-energy food Supplemental Figures 1–5, Supplemental Tables 1–4, and Supplemental pictures and reduced energy intake during an ad libitum meal. These Methods are available from the “Online Supporting Material” link in the observations were not related to changes in blood peptide YY (PYY), online posting of the article and from the same link in the online table of glucagon-like peptide 1 (GLP-1), glucose, or insulin concentrations. contents at http://ajcn.nutrition.org. Conclusion: Our results suggest that colonic propionate production These authors contributed equally to this work as senior authors. may play an important role in attenuating reward-based eating behavior *To whom correspondence should be addressed. E-mail: tony.goldstone@ via striatal pathways, independent of changes in plasma PYY and GLP-1. imperial.ac.uk (AP Goldstone), g.frost@imperial.ac.uk (GS Frost). This trial was registered at clinicaltrials.gov as NCT00750438. Am J Received December 7, 2015. Accepted for publication April 11, 2016. Clin Nutr 2016;104:5–14. First published online May 11, 2016; doi: 10.3945/ajcn.115.126706. Am J Clin Nutr 2016;104:5–14. Printed in USA. 5 6 BYRNE ET AL. There is increasing evidence that metabolites produced by the Participants colonic microbiota may affect central appetite regulation (5–7). Subjects were recruited via public advertisement and Resistant starch (RS) supplementation alters activation in hy- a healthy volunteer database. Healthy men aged 18–65 y with pothalamic nuclei and gene expression of neuropeptides in- 2 BMI (in kg/m ) 20–35 were eligible for inclusion. Exclusion volved in appetite regulation in rodents (5, 6). The consumption criteria included the following: weight gain or loss .3kgin the of nondigestible carbohydrates (NDCs) also reduces energy in- previous 3 mo, any chronic illness or gastrointestinal disorder, take and weight gain in animal models (8–10). Several physio- history of drug or alcohol abuse in the previous 2 y, use of an- logic benefits associated with the consumption of RS and other tibiotics or medications likely to interfere with energy homeo- NDCs may be mediated through the actions of their fermenta- stasis in the previous 3 mo, claustrophobia, contraindications for tion products, namely, short-chain fatty acids (SCFAs). The MRI scanning, daily smoking, gluten or lactose intolerance, principal SCFAs produced via bacterial fermentation are acetate, consumption of a vegan or vegetarian diet, or depression as propionate, and butyrate, present in the colon in the approximate assessed by a Beck Depression Inventory II score .10 (20). molar ratio of 60:20:20 (11). Our research group demonstrated that increasing circulating acetate directly suppresses appetite Food supplements via central hypothalamic mechanisms in rodents (7). Our recent findings from human studies suggest that propionate may also be IPE designed for targeted delivery of propionate to the colon an important SCFA contributing to appetite regulation (12). The was produced as previously described (12). Inulin was chosen as acute intake of an inulin-propionate ester (IPE), which selec- a control supplement, with the use of the same inulin used to tively increases colonic propionate production, reduced ad prepare both the IPE and control supplements. This controlled for libitum energy intake and increased plasma concentrations of residual fermentation of the backbone NDC. In vitro fermenta- the anorexigenic gut hormones glucagon-like peptide 1 (GLP-1) tions of IPE and inulin suggest comparable increases in acetate and peptide YY (PYY), supporting results of in vitro experi- and butyrate production; thus, any differences in our outcome ments (12, 13). Furthermore, a long-term elevation in colonic measures can be attributed to the preferential increase in pro- propionate production protected against weight gain and re- pionate production with IPE (12). duced hepatic lipid content (12). The exogenous administration of GLP-1 or its analogs and/or Study day protocol PYY reduces brain reward system responses to viewing food pictures in humans (4, 14). However, to date, to our knowledge, Twenty healthy men participated in this randomized, placebo- there are no studies demonstrating an effect of SCFAs on human controlled, within-subject, single-blind crossover study. Subjects brain food-reward responses to influence eating behavior. In the attended 2 separate study visits $6 d apart after an overnight present study, we examined the effect of an acute increase in fast. Subjects were asked to record their dietary intake; avoid colonic propionate production on energy intake and brain regions caffeine, alcohol, and strenuous exercise for 24 h before each involved with reward processing and hedonic eating, includ- visit; and not smoke cigarettes for $48 h before each visit. ing caudate, nucleus accumbens, amygdala, anterior insula, and Study visits were conducted between April and December orbitofrontal cortex (OFC) (15, 16), in healthy nonobese men in 2014 in the National Institute for Health Research/Wellcome a randomized crossover design (Figure 1). We used fMRI to Trust Imperial Clinical Research Facility, Hammersmith Hos- measure activation by the BOLD signal in these regions of in- pital, London, United Kingdom. Weight, height, and body fat terest during an established food evaluation task that used high measurements were collected with the use of bioimpedance energy (HE)– and low energy (LE)–density food pictures (pri- analysis (BC-418 analyzer; Tanita UK). At each visit, subjects mary outcome measure) (3, 17–19). We hypothesized that in- completed a Positive and Negative Affect Schedule to measure creasing colonic propionate production after intake of IPE would mood during the previous week (21). Serial venous blood reduce anticipatory reward responses during evaluation of food samples were collected via a peripheral cannula to assay plasma pictures, a measure of food cue reactivity, compared with control and serum metabolite and hormone concentrations over study inulin via the stimulation of the anorexigenic gut hormones GLP-1 visits (Figure 1). and PYY (4), and would reduce ad libitum energy intake. Breath hydrogen concentration, a marker of colonic fermen- tation (22), was measured with the use of a handheld breath hydrogen analyzer (EC60 Gastrolyser Breath Hydrogen Monitor; Bedfont Scientific), and twelve 100-mm visual analog scales METHODS were completed to assess serial subjective appetite and mood Further details are given in Supplemental Methods. The ratings (Figure 1). study was approved by the West London Research Ethics At 0 min, a standard breakfast containing 10 g IPE (treatment) Committee (08/H0707/99) (NCT00750438). or 10 g inulin (control) was provided to subjects in a randomized order (via sealed envelope). Breakfast was a chocolate milkshake and snack bar (574.5 kcal; 86.4 g carbohydrate, 18.8 g fat, 14.7 g Abbreviations used: AMV, auditory–motor–visual; aROI, anatomical protein, and 3.2 g fiber). Lunch (180 min) was a cheese sandwich region of interest; DRD2, dopamine receptor D2; ED, energy density; EPI, and snack bar (558 kcal; 62.3 g carbohydrate, 24.9 g fat, 21.7 g echoplanar imaging; fROI, functional region of interest; GLP-1, glucagon- protein, and 2.8 g fiber). like peptide 1; HE, high-energy; IPE, inulin-propionate ester; LE, low- At 300 min, subjects completed a 60-min MRI session (Sie- energy; NDC, nondigestible carbohydrate; OFC, orbitofrontal cortex; mens 3T Verio MRI scanner) in the Imperial Clinical Imaging PYY, peptide YY; RS, resistant starch; RYGB, Roux-en-Y gastric bypass; SCFA, short-chain fatty acid. Facility. This time point was chosen based on previous results PROPIONATE AND STRIATAL FOOD REWARD RESPONSES 7 FIGURE 1 Study day protocol. Overview of timings of blood sampling, VAS ratings, breath hydrogen recordings, and scanning protocol. AMV, auditory– motor–visual; IPE, inulin-propionate ester; T1, T1 anatomical scan; VAS, visual analog scale. Adapted from reference 17 with permission. from an acute study that suggest successful delivery of IPE to to ensure exclusion of data for subjects who may not be at- the colon and increased plasma gut hormone concentrations after tending to the task. 240 min (12). AMV control fMRI paradigm Finally, a savory meal of tomato and mozzarella pasta bake (per 100 g: 129 kcal; 17.0 g carbohydrate, 3.9 g fat, 4.8 g protein, An AMV control task was performed to exclude nonspecific and 3.4 g fiber) was served to subjects. Subjects were instructed to changes in the BOLD signal between visits, as previously de- eat until they felt comfortably full. Five of the first 12 subjects scribed (17–19). In a block design, subjects performed 2 of each who completed the study consumed all of the food presented at of the following tasks simultaneously: 1) listening to a story, 2) the meal. As a result, data on food intake for these 5 subjects were tapping their right index finger once every second, or 3) removed from analysis of ad libitum food consumption and the watching a 4-Hz color-flashing checkerboard. amount of food presented to the final 8 subjects was increased. Image processing fMRI scanning protocol fMRI data processing was carried out with the use of FEAT version 6.00, part of FSL (Functional Magnetic Resonance All subjects underwent an MRI scan from 300 to 360 min as Imaging of the Brain (FMRIB) software library; www.fmrib.ox. previously described (17–19). After an initial practice run with ac.uk/fsl), including field map–based EPI unwarping and tem- the use of pictures of animals, subjects had a resting-state fMRI poral derivative and motion variables as covariates in the general scan lasting 10 min followed by the food picture fMRI paradigm linear model, boundary-based registration of EPI to high reso- at 320 min (Figure 1). Subjects had an auditory–motor–visual lution structural space, and nonlinear registration to standard (AMV) fMRI task at 350 min, followed by collection of struc- space. Higher-level analysis used a fixed-effect model to com- tural magnetic resonance brain scans, including high-resolution bine the 2 runs to determine activation for the following contrasts: T1-weighted scans for image registration (Figure 1). Whole- HE food . object, LE food . object, or any food (HE or LE) brain fMRI data were acquired with T2*-weighted gradient- compared with objects. Similar analysis was performed for the echo echoplanar imaging (EPI). single-run AMV paradigm including the onsets of each task (auditory, motor, and visual) to contrast activation during per- Food evaluation fMRI paradigm formance of each task with that when it was not being performed. During the fMRI food picture paradigm, 4 types of color Whole-brain analysis photographs were presented in a block design (6 pictures/block; each image displayed for 2500 ms) split across 2 runs as follows: Whole-brain analysis was performed separately with the use of 1) 60 HE foods (e.g., pizza, cakes, and chocolate), 2)60LE FEAT v6.00 for the HE and LE contrasts with the use of a paired t foods (e.g., salads, vegetables, and fish), 3) 60 non–food-related test to identify regions with significant differences in the BOLD household objects (e.g., furniture and clothing), and 4) 180 signal between control inulin and IPE treatments with the use of blurred images of the other pictures (as a low-level baseline) in both a voxel-wise correction false discovery rate, P , 0.05, and blocks after every food or object block (17–19). While each a cluster-wise correction family-wise error, Z . 2.3, P , 0.05. image was on display in the scanner, subjects were asked to rate simultaneously how appealing each picture was to them with the fMRI regions of interest use of a 5-button hand-held keypad (1 = not at all; 5 = a lot). Exclusion of subjects with a failure to rate .10% of the food Functional regions of interest (fROIs) were determined from and object pictures at either study visit was a predefined cutoff average group activation in a separate cohort of 21 nonobese 8 BYRNE ET AL. TABLE 1 healthy subjects from a previous study (17) for any food (HE or Subject characteristics LE) . object in the nucleus accumbens, amygdala, insula (an- terior), caudate, and OFC brain regions (Supplemental Figure 1 All subjects fMRI analysis and Supplemental Table 1). Similar fROIs were made for the Male 20 (100) 18 (100) AMV control task as follows: superior temporal gyrus posterior European Caucasian 18 (90) 17 (94) division for the secondary auditory cortex; precentral gyrus for Age, y 52 (26, 61) 55 (27, 61) the primary motor cortex; and lingual gyrus for the primary Weight, kg 79.0 6 1.5 78.5 6 1.5 visual cortex (Supplemental Figure 2). An anatomic region of BMI, kg/m 25.2 6 0.5 24.9 6 0.5 interest for the hypothalamus was also generated with the use of Body fat, % 20.6 6 1.1 20.6 6 1.1 the mean of all anatomical T1 scans for the subjects in the BDI-II (maximum 1 (0, 3.3) 1 (0, 3.8) score 63) current study. Time between visits, d 7 (7, 17) 7 (7, 13.3) Values are means 6 SEMs, medians (IQRs), or n (%). Age and an- Comparison of fMRI activation between groups thropometric data are means of first and second study visit measurements. The mean bilateral BOLD signal within each a priori fROI was 2 BDI-II, Beck Depression Inventory II. then extracted for each individual subject for the HE and LE contrasts at each visit to measure differences between treatments. Similar analysis was performed to compare activation in the either inulin or IPE and stayed significantly elevated until the end of the study visit (Figure 2). This suggests that the fermentation relevant fROIs between treatments in the AMV task. of IPE and the release of propionate in the colon occurred in a time course similar to that previously reported (12). As ex- Composite appetite score pected, in a repeated-measures ANOVA, including treatment A composite score was calculated with the use of the following and time as within-subject factors, there was a significant formula (23): [hunger + (100 – fullness) + desire to eat + appetite treatment 3 time interaction in that breath hydrogen concen- for meal] O 4. trations were significantly higher after receiving the control in- ulin than with IPE [F(1, 19) = 3.83, P , 0.01] because of the Blood sample preparation greater amount of fermentable carbohydrate in the control inulin Ten milliliters of blood was collected at each time point for than in the IPE (10 g compared with 7.3 g). assay of plasma glucose (EDTA), serum insulin, and plasma gut hormones (5 mL in lithium heparin tube containing 100 mL Ad libitum energy intake aprotinin protease inhibitor; Nordic Pharma UK). All tubes were centrifuged at 2590 3 g for 10 min at 48C. Samples were sep- Data on energy intake for 5 subjects were removed from arated and frozen at 2208C until analysis. analysis of ad libitum energy intake because these subjects consumed all presented food during one or both visits (see Metabolic and hormone analysis Methods). IPE treatment significantly reduced energy intake by 9.5% 6 5.3% [control 810.4 6 83.4 kcal (95% CI: 631.6, 989.2 Glucose analysis was performed at the Department of Bio- kcal) compared with IPE 711.1 6 79.9 kcal (95% CI: 539.7, chemistry, Hammersmith Hospital, with the use of a ci8200 882.6 kcal), t(14) = 2.41, P = 0.030] (Figure 3). analyzer enzymatic method (Abbott Diagnostics). A human in- sulin radioimmunoassay kit (Millipore) was used for insulin analysis according to manufacturer’s guidelines with 50 mL BOLD signal in food evaluation fMRI task serum. PYY and GLP-1 were measured with the use of previ- ously established in-house specific and sensitive radioimmuno- In 2-factor repeated-measures ANCOVA, including energy assay (24, 25). SCFAs were measured at the Department of density (ED) of food pictures and treatment as within-subject Cancer and Surgery with the use of an Agilent 7000C Triple factors and visit order as a covariate, there was a significant ED 3 Quadrupole GC/MS System according to a previously published treatment interaction for the BOLD signal in the caudate [F(1, method (26). Values are expressed as means 6 SEMs. 16) = 8.86, P = 0.009, Bonferroni correction P = 0.045 for multiple regions of interest] and nucleus accumbens [F(1, 16) = 10.81, P = 0.005, Bonferroni correction P = 0.025] that favored RESULTS HE foods (Figure 4A and B), but not in the amygdala [F(1, 16) Participants = 1.65, P = 0.22], anterior insula [F(1, 16) = 2.65, P = 0.12], or OFC [F(1, 16) = 0.76, P = 0.40] (Figure 4C–E). Subject characteristics are given in Table 1. Two of the 20 In the caudate (Figure 4A), post hoc analysis revealed that IPE men were removed from fMRI analysis because of poor com- treatment significantly reduced the BOLD signal to HE foods pliance with the picture evaluation task (predefined as failure to [effect size: 20.078 6 0.032 (95% CI: 20.147, 20.009), P = rate overall .10% of the food and object pictures during either 0.029] but not to LE foods [effect size: 20.057 6 0.037 (95% study visit), leaving 18 subjects with data for fMRI analysis. CI: 20.134, 0.021), P = 0.14]. However, in post hoc analysis in the nucleus accumbens (Figure 4B), IPE treatment did not sig- Breath hydrogen nificantly reduce the BOLD signal to HE foods [effect size: Breath hydrogen concentrations were significantly elevated 20.082 6 0.055 (95% CI: 20.198, 0.035), P = 0.16] or to LE above baseline concentrations 210 min after subjects received foods [effect size: 20.064 6 0.038 (95% CI: 20.144, 0.016), PROPIONATE AND STRIATAL FOOD REWARD RESPONSES 9 BOLD signal in control fMRI task An AMV control task was performed to look for nonspecific changes in the BOLD signal between treatments, as previously described (17–19). There was no significant difference in the BOLD signal in any fROI between treatments during the control fMRI task (1-factor repeated-measures ANCOVA including visit order as covariate, P = 0.15–0.86; Figure 4F). Food appeal ratings and reaction time In 2-factor repeated-measures ANCOVA, including ED of food pictures and treatment as within-subject factors and visit FIGURE 2 Breath hydrogen concentrations after IPE or control inulin. order as a covariate, there was a significant ED 3 treatment Values are medians (IQRs), n = 20. The dotted vertical line signifies the time interaction for food appeal ratings, with a greater effect for HE point after which .80% IPE previously has been shown to enter the colon foods [F(1, 16) = 5.50, P = 0.032] (Figure 5A). Within HE food (12). Breath hydrogen concentrations after control inulin (y) or IPE (*) compared with baseline concentrations with the use of paired-samples t tests subcategories, there was no significant HE food subcategory 3 ,y ,yyy (calculations performed on normalized data): * P , 0.05, *** P , treatment interaction for food appeal ratings [F(2, 16) = 2.49, 0.005. IPE, inulin-propionate ester; ppm, parts per million. P = 0.099] (Figure 5B). However, independent of HE food sub- category, HE foods were rated significantly less appealing when P = 0.11], although the direction of the IPE effect was similar to patients received IPE than when they received the control [F(1, that for the caudate. 16) = 4.69, P = 0.046] (Figure 5B). By contrast, there was no Independent of ED, there was no significant effect of treatment difference in appeal ratings of object pictures between treat- on the BOLD signal in the amygdala [F(1, 16) = 0.54, P = 0.47], ments when including visit order as a covariate [F(1, 16) = 0.02, anterior insula [F(1, 16) = 0.02, P = 0.89], or OFC [F(1, 16) = P = 0.88]. 1.56, P = 0.23] (Figure 4C–E). There was no significant ED 3 treatment interaction for the There was no significant correlation between the difference in reaction time for subjects to rate the food pictures [F(1, 16) = the BOLD signal to HE foods alone, or any food (HE or LE), in 0.24, P = 0.63] (Figure 5C). However, independent of ED of the caudate (r = 20.11, P = 0.74; and r = 20.41, P = 0.18, food pictures, IPE treatment significantly increased the reaction respectively) or nucleus accumbens (r = 20.19, P = 0.56; and time to food pictures [F(1, 16) = 13.82, P = 0.002] (Figure 5C). r = 20.35, P = 0.27, respectively) between treatments and the Within HE food subcategories, there was no significant HE food difference in energy intake between treatments (n = 13). subcategory 3 treatment interaction for reaction time to food In 2-factor repeated-measures ANCOVA, including ED of food pictures [F(2, 16) = 1.57, P = 0.22] (Figure 5D). However, in- pictures and treatment as within-subject factors and visit order as dependent of HE food subcategory, the reaction time for HE a covariate, there was no significant ED 3 treatment interaction for food pictures was significantly increased after subjects received the BOLD signal in the hypothalamus anatomic region of interest IPE [F(1, 16) = 14.54, P = 0.002] (Figure 5D). By contrast, there [F(1, 16) = 1.61, P = 0.22] (Supplemental Figure 3). Independent was no difference in reaction times for subjects to rate object of ED, there was also no significant effect of treatment on the pictures between treatments when including visit order as a co- BOLD signal in the hypothalamus [F(1, 16) = 1.16, P = 0.30]. variate [F(1, 16) = 2.40] (P = 0.14). In whole-brain analysis, there were no significant regional differences in the BOLD signal for either the HE or LE food Blood hormones and metabolites contrasts surviving correction for multiple comparisons with the use of a voxel-wise false discovery rate of P , 0.05 or a cluster- There was no significant difference in the AUC for 0–360 min wise family-wise error of Z . 2.3, P , 0.05. plasma PYY, GLP-1, or glucose or serum insulin after subjects FIGURE 3 Energy intake at ad libitum meal after IPE or control inulin. Values are mean 6 SEM absolute energy intake after control inulin or IPE (paired-samples t test: *P , 0.05, n = 15) (A) and individual percentage differences in energy intake between IPE and control inulin (B). The horizontal solid line in panel B represents the mean 9.5% reduction in energy intake. IPE, inulin-propionate ester. 10 BYRNE ET AL. FIGURE 4 BOLD signal during food evaluation and AMV control fMRI tasks after consumption of IPE or control inulin. Magnitude of the BOLD signal (percentage) in brain reward systems in the caudate (A), nucleus accumbens (B), anterior insula (C), amygdala (D), and OFC (E) during evaluation of pictures of low-ED foods (minus objects contrast) or high-ED foods (minus objects contrast). Bilateral posterior division of superior temporal gyrus in auditory task, left precentral gyrus in motor task, and bilateral lingual gyrus in visual task after control inulin or IPE, n = 18 (F). Results compared with control inulin with the use of 2-factor (A–E) and 1-factor (F) repeated-measures ANCOVA with a post hoc Fisher least-significant difference test while including visit order as a covariate, *P , 0.05; **P , 0.01. AMV, auditory–motor–visual; ED, energy density; IPE, inulin-propionate ester; OFC, orbitofrontal cortex; preCG, precentral gyrus; postSTG, posterior division of superior temporal gyrus. received IPE compared with control inulin (Supplemental BOLD signal or hedonic response to food pictures, including in Figure 4 and Supplemental Table 2). Furthermore, 2-factor BMI, percentage body fat, mood, total energy intake on the repeated-measures ANOVA revealed no time 3 treatment in- previous day, ratings of nausea, sleepiness, stress or anxiety, or teractions for plasma PYY, GLP-1, or glucose or serum insulin head motion during the fMRI task (Supplemental Table 3). (P = 0.25–0.58). Correlations between outcome measures Serum SCFAs As expected, the change in energy intake between treatments was positively correlated with the change in composite appetite Compared with baseline, there was no significant increase in visual analog scale ratings between treatments (Supplemental serum acetate or propionate concentrations 240 min after subjects Table 4). However, there was no significant correlation between received IPE or control inulin (Table 2). For serum butyrate, elevated colonic propionate on the BOLD signal to HE food in there was a significant increase in concentrations 240 min after the caudate or nucleus accumbens, or in the mean of both re- subjects received both IPE and control inulin compared with gions, and the effect of increased colonic propionate on HE food baseline. There was no difference in SCFA concentrations be- appeal, or in composite appetite visual analog scale ratings tween treatments at baseline (P = 0.25–0.87) or at 240 min (P = (Supplemental Table 4). 0.10–0.88). Confounding variables DISCUSSION There was no significant effect of IPE treatment on composite We used an established fMRI food evaluation paradigm to appetite visual analog scale ratings (Supplemental Figure 5). assess the effects of elevated colonic propionate on brain re- There were no significant differences between treatment visits in sponses during food picture evaluation in a priori regions of potential confounding variables that may have affected the interest previously associated with reward processing and PROPIONATE AND STRIATAL FOOD REWARD RESPONSES 11 FIGURE 5 Food picture appeal ratings and rating reaction times after consumption of IPE or control inulin. Magnitude of appeal ratings (1 = not at all; 5 = a lot) (A and B) and reaction times to rate food pictures of varying energy densities as scored with the use of a hand-held button box (C and D) after control inulin or IPE (n = 18). Results given for low-energy or HE foods (A and C) and different categories of HE foods (chocolate, other sweet, and nonsweet savory) (B and D). Results compared with control inulin with the use of 2-factor repeated-measures ANCOVA with post hoc Fisher least-significant difference test while including visit order as a covariate, *P , 0.05; ***P , 0.005. ED, energy density; HE, high-energy; IPE, inulin-propionate ester. hedonic eating behavior. An acute increase in colonic propionate the ventral striatum BOLD signal during evaluation of HE reduced the BOLD signal during an evaluation of food pictures in compared with LE food pictures, and a preferential reduction in the caudate (dorsal striatum) and nucleus accumbens (ventral the appeal of HE foods, when an fMRI paradigm identical to striatum) in nonobese men, which was greater for HE than for LE that of the current study is used (3). The reduced ventral striatum foods. Indeed, in the caudate, elevated colonic propionate spe- BOLD signal to HE food pictures in the fed compared with cifically reduced the BOLD signal during evaluation of HE but fasted state has also been correlated with a subsequent reduction not LE food pictures. Increased colonic propionate production in ad libitum energy intake (28). Similarly, satiation decreases also reduced the appeal of HE food pictures and prolonged the BOLD responses to food taste in the nucleus accumbens (31), time taken to rate their appeal, an implicit measure that suggested whereas duration of food deprivation correlates with a greater reduced wanting (17, 27). Furthermore, this reduced activation in caudate BOLD signal in response to actual and anticipated re- striatal brain reward systems was accompanied by a reduction in ceipt of palatable food (29). Satiation also decreases regional ad libitum energy intake. This is the first time, to our knowledge, cerebral blood flow at rest, another marker of neuronal activity, that an acute increase in colonic propionate or any other SCFA in the caudate and nucleus accumbens (32). Greater activation in has been shown to significantly reduce anticipatory food hedonic the nucleus accumbens to food pictures is predictive of future responses and associated BOLD signal changes in brain regions snack consumption and reduced weight loss success in an obe- associated with reward processing in humans. sity lifestyle intervention (30, 33). Alterations in caudate acti- Changes in striatal the BOLD signal to food cues previously vation to actual or anticipated receipt of HE palatable food have have been associated with physiologically relevant alterations in been linked to genetic variations in the dopamine receptor D2 food reward processing and eating behavior (3, 28–30). In the (DRD2) gene, which is highly expressed in the striatum and satiated fed compared with fasted state, there is a reduction in linked to increased BMI, familial risk of obesity, and prospective TABLE 2 Serum SCFA concentrations after consumption of IPE or control inulin mmol/L Control inulin IPE D 240 min 3 3 4 0 min 240 min tP 0 min 240 min tP tP Acetate 83.9 6 2.8 96.8 6 7.8 21.72 0.10 86.4 6 4.1 95.4 6 7.2 21.19 0.25 0.49 0.63 Propionate 6.8 6 0.3 7.8 6 0.5 21.64 0.12 7.4 6 0.3 8.3 6 0.5 21.57 0.13 0.16 0.87 Butyrate 5.4 6 0.2 6.1 6 0.3 22.50 0.02 5.3 6 0.2 6.9 6 0.4 23.64 ,0.01 21.87 0.08 Values are means 6 SEMs. n = 20. IPE, inulin-propionate ester; SCFA, short-chain fatty acid. Represents concentrations at 240 min minus baseline values. For 0 min compared with 240 min calculated with the use of paired-samples t tests within each treatment. For D concentrations after control inulin compared with IPE calculated with the use of paired-samples t tests 240 min between treatments. 12 BYRNE ET AL. weight gain (34–36). In addition, after Roux-en-Y gastric bypass bound propionate from IPE is absorbed from the gut and is (RYGB) surgery, obese patients have lower activation in the available systemically (12). The significant increase in butyrate caudate and nucleus accumbens when HE foods are evaluated, observed after both treatments could be explained by the inter- and have lower HE food appeal than patients after gastric banding conversion of acetate to butyrate from microbial fermentation of surgery (18). Acute suppression of plasma PYY and GLP-1 in inulin (41). However, it is unclear why this would be reflected in patients after RYGB surgery increases food reward responses in serum butyrate when splanchnic extraction has been shown to the nucleus accumbens (19). RYGB has been associated with balance gut butyrate production (42). increased colonic propionate production in animal models (37). In addition to reduced striatal responses to food pictures, we This evidence supports a role of the striatum in altered reward observed a 9.5% reduction in energy intake after subjects re- processing and food consumption patterns. It suggests that in- ceived IPE, in line with previous observations (12). However, creased colonic propionate may modulate the engagement of this there was no difference in plasma PYY and GLP-1 concen- brain-reward circuit, resulting in a reduction in energy intake, trations between treatments, a finding that is not in line with our although we could not demonstrate a direct correlation between original hypothesis. It previously has been demonstrated that changes in the BOLD signal and energy intake in our study. an increased intake of NDCs and colonic SCFA production Previous research in animal models supports the role of NDCs can improve body composition and reduce energy intake in- and SCFAs in central appetite regulation. RS supplementation dependent of changes in peripheral gut hormone concentrations reduces activity in hypothalamic appetite regulation centers as in mice (6, 7, 43). This suggests that alternative mechanisms are assessed by manganese-enhanced MRI and stimulates anorexi- responsible for the appetite-regulating effects associated with genic hypothalamic pro-opiomelanocortin expression in rodents the consumption of NDCs and SCFAs, and for the changes in the (5, 6). Acetate itself suppresses appetite via central hypothalamic striatal BOLD signal and food appeal during food picture mechanisms (7) and also has been shown to have other central evaluation in the current study. Propionate is a gluconeogenic effects (38). By contrast, no known studies have investigated the precursor, both at the gut epithelium and liver, and ruminant effect of SCFAs on central appetite regulation in humans. We did studies consistently have demonstrated that an elevated portal not find any significant effect of elevated colonic propionate on concentration of propionate depresses energy intake, which the hypothalamic BOLD signal during food picture evaluation in is abolished with hepatic vagotomy or total hepatic innerva- the current study. However, BOLD imaging in the hypothalamus tion (44, 45). However, we did not identify any difference in has poor reliability related to its small-size, partial-volume effects blood glucose or insulin concentrations between treatments, in because of close proximity to the third ventricle and cerebro- agreement with previous reports (12). Other possible mechanisms spinal fluid spaces, and artifact from the internal carotid artery. driving our observations may be via the induction of vagal Furthermore, an interpretation of changes in the overall BOLD signaling in the gut or portal vein through stimulation of free fatty signal in the hypothalamus may be complicated by the multiple acid receptor 3 (46–48). Further work is needed to gain a better smaller hypothalamic nuclei containing both orexigenic and understanding of the gut–liver–brain signaling pathways in re- anorexigenic feeding neurons. sponse to increased colonic propionate. This would provide in- One of the major limitations of NDC supplementation is that formation about whether our observations are a direct effect of large doses are needed to observe effects that are in line with propionate on neural pathways or a secondary response mech- those noted in animal studies. For example, our research group anism to propionate metabolism. previously has shown that .35 g NDC/d is needed to suppress We believe the major strengths of our study are the following: 1) appetite and stimulate an increase in plasma PYY concentrations the use of fMRI, a well-validated noninvasive measure of human (39). However, the development of IPE uniquely allows for the brain activity; 2) the incorporation of a well-established food targeted delivery of a known amount of propionate directly to evaluation paradigm that is sensitive to peripheral signals the colon, which normally only would be obtained from a high- influencing appetite and reward-based eating behavior, such as fiber diet, without the associated gastrointestinal side effects gut hormones and after bariatric surgery (17–19); 3) the exclu- (e.g., abdominal bloating or flatulence). We have previously sion of nonspecific effects on the BOLD signal with the use of shown with the use of a C-labeled variant of IPE that .80% of a control fMRI task; and 4) the within-subject crossover design. the bound propionate is released coincident with breath hydro- A limitation of our study is the lack of energy intake data for 5 gen. This suggests delivery of the majority of bound propionate subjects, which may have reduced the ability to detect correla- to the colon (12). We estimate that a 10-g dose of IPE delivers tions between outcome measures. Another limitation was the 2.36 g propionate to the colon, which is 2.5 times habitual daily inclusion of only a nonobese male cohort. The findings will need propionate production. In the current study, the breath hydrogen confirmation in an obese cohort and in women, who may have data suggests significant fermentation by 210 min and at the altered reward and emotional responses to food. The effect of time of the MRI session. Despite this, we were unable to detect long-term IPE supplementation on striatal reward responses also any difference in serum propionate between treatments. Our remains to be elucidated. current measurement may have lacked sensitivity to record In conclusion, elevated colonic propionate significantly re- minor increases in peripheral circulatory propionate, particularly duced the striatal BOLD signal during evaluation of HE foods, when measured at a single postprandial time point. This is un- reduced HE food picture appeal, and reduced energy intake at an surprising, because .95% propionate present in the portal vein ad libitum meal in nonobese men, an effect that was independent is extracted by the liver, resulting in only a minor fraction of changes in plasma PYY, GLP-1, and glucose and serum in- reaching the peripheral circulation (40). Nevertheless, we have sulin. These results suggest that colonic propionate may play an previously demonstrated a significant increase in propionate C important role in human appetitive and reward-based eating enrichment in the peripheral circulation, revealing that the behavior at least in part through brain striatal pathways. PROPIONATE AND STRIATAL FOOD REWARD RESPONSES 13 We thank Tom Clarkson for the synthesis of the inulin-propionate ester and 18. Scholtz S, Miras AD, Chhina N, Prechtl CG, Sleeth ML, Daud NM, Milena Rundle, Amin Alamshah, Katerina Petropoulou, and Annette Henry Ismail NA, Durighel G, Ahmed AR, Olbers T. Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than for their assistance with the radioimmunoassay. after gastric banding. Gut 2014;63:891–902. The authors’ responsibilities were as follows—APG and GSF: designed 19. Goldstone AP, Miras AD, Scholtz S, Jackson S, Neff KJ, Pénicaud the study; CSB, ESC, and HA: recruited the subjects; DJM, TP, and CT: L, Geoghegan J, Chhina N, Durighel G, Bell JD. Link between in- provided the materials; CSB, ESC, HA, NC, JF, CI, and AB: collected the creased satiety gut hormones and reduced food reward following data; CSB, ESC, APG, and GSF: analyzed the data; CSB, ESC, DJM, IG-P, gastric bypass surgery for obesity. J Clin Endocrinol Metab 2016; SF, EH, APG, and GSF: interpreted the data and wrote the manuscript; and 101: 599–609. all authors: read and approved the final manuscript. A patent application for 20. Beck AT, Steer RA, Ball R, Ranieri WF. Comparison of Beck De- “Compounds and their effects on appetite control and insulin sensitivity” pression Inventories-IA and-II in psychiatric outpatients. J Pers Assess surrounding the use of inulin-propionate ester has been filed by DJM and 1996;67:588–97. 21. Killgore WD, Yurgelun-Todd DA. Affect modulates appetite-related GSF (WO2014020344). None of the other authors reported a conflict of brain activity to images of food. Int J Eat Disord 2006;39:357–63. interest related to the study. 22. Levitt MD. Production and excretion of hydrogen gas in man. N Engl J Med 1969;281:122–7. 23. Woodend DM, Anderson GH. Effect of sucrose and safflower oil preloads on short term appetite and food intake of young men. Appetite REFERENCES 2001;37:185–95. 1. Murphy KG, Bloom SR. Gut hormones and the regulation of energy 24. Adrian TE, Ferri G, Bacarese-Hamilton A, Fuessl H, Polak J, Bloom S. homeostasis. Nature 2006;444:854–9. Human distribution and release of a putative new gut hormone, peptide 2. Dagher A. Functional brain imaging of appetite. Trends Endocrinol YY. Gastroenterology 1985;89:1070–7. Metab 2012;23:250–60. 25. Kreymann B, Ghatei M, Williams G, Bloom S. Glucagon-like peptide- 3. Goldstone AP, Prechtl de Hernandez CG, Beaver JD, Muhammed K, 1 7-36: a physiological incretin in man. Lancet 1987;2:1300–4. Croese C, Bell G, Durighel G, Hughes E, Waldman AD, Frost G. 26. Moreau NM, Goupry S, Antignac J, Monteau F, Le Bizec B, Champ Fasting biases brain reward systems towards high-calorie foods. Eur J M, Martin L, Dumon H. Simultaneous measurement of plasma con- Neurosci 2009;30:1625–35. centrations and 13 C-enrichment of short-chain fatty acids, lactic acid 4. De Silva A, Salem V, Long CJ, Makwana A, Newbould RD, Rabiner EA, and ketone bodies by gas chromatography coupled to mass spec- Ghatei MA, Bloom SR, Matthews PM, Beaver JD. The gut hormones trometry. J Chromatogr B Analyt Technol Biomed Life Sci 2003;784: PYY 3-36 and GLP-1 7-36 amide reduce food intake and modulate brain 395–403. activity in appetite centers in humans. Cell Metab 2011;14:700–6. 27. Finlayson G, King N, Blundell J. The role of implicit wanting in re- 5. Shen L, Keenan MJ, Martin RJ, Tulley RT, Raggio AM, McCutcheon lation to explicit liking and wanting for food: implications for appetite KL, Zhou J. Dietary resistant starch increases hypothalamic POMC control. Appetite 2008;50:120–7. expression in rats. Obesity (Silver Spring) 2009;17:40–5. 28. Fletcher PC, Napolitano A, Skeggs A, Miller SR, Delafont B, Cam- 6. So P-W, Yu W-S, Kuo Y-T, Wasserfall C, Goldstone AP, Bell JD, Frost bridge VC, de Wit S, Nathan PJ, Brooke A, O’Rahilly S. Distinct G. Impact of resistant starch on body fat patterning and central appetite modulatory effects of satiety and sibutramine on brain responses to regulation. PLoS One 2007;2:e1309. food images in humans: a double dissociation across hypothalamus, 7. Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L, amygdala, and ventral striatum. J Neurosci 2010;30:14346–55. Anastasovska J, Ghourab S, Hankir M, Zhang S. The short-chain fatty 29. Stice E, Burger K, Yokum S. Caloric deprivation increases responsivity acid acetate reduces appetite via a central homeostatic mechanism. Nat of attention and reward brain regions to intake, anticipated intake, and Commun 2014;5:3611. images of palatable foods. Neuroimage 2013;67:322–30. 8. Cani PD, Neyrinck AM, Maton N, Delzenne NM. Oligofructose pro- 30. Lawrence NS, Hinton EC, Parkinson JA, Lawrence AD. Nucleus motes satiety in rats fed a high-fat diet: involvement of glucagon-like accumbens response to food cues predicts subsequent snack con- peptide-1. Obes Res 2005;13:1000–7. sumption in women and increased body mass index in those with re- 9. Delmée E, Cani PD, Gual G, Knauf C, Burcelin R, Maton N, Delzenne duced self-control. Neuroimage 2012;63:415–22. NM. Relation between colonic proglucagon expression and metabolic re- 31. Thomas JM, Higgs S, Dourish CT, Hansen PC, Harmer CJ, McCabe C. sponse to oligofructose in high fat diet-fed mice. Life Sci 2006;79:1007–13. Satiation attenuates BOLD activity in brain regions involved in reward 10. Arora T, Loo RL, Anastasovska J, Gibson GR, Tuohy KM, Sharma RK, and increases activity in dorsolateral prefrontal cortex: an fMRI study Swann JR, Deaville ER, Sleeth ML, Thomas EL. Differential effects of in healthy volunteers. Am J Clin Nutr 2015;101:697–704. two fermentable carbohydrates on central appetite regulation and body 32. Gautier JF, Parigi A, Chen K, Salbe AD, Bandy D, Pratley RE, composition. PLoS One 2012;7:e43263. Ravussin E, Reiman EM, Tataranni PA. Effect of satiation on brain 11. Cummings JH, Pomare E, Branch W, Naylor C, Macfarlane G. Short activity in obese and lean women. Obes Res 2001;9:676–84. chain fatty acids in human large intestine, portal, hepatic and venous 33. Murdaugh DL, Cox JE, Cook EW, Weller RE. fMRI reactivity to high- blood. Gut 1987;28:1221–7. calorie food pictures predicts short-and long-term outcome in a weight- 12. Chambers ES, Viardot A, Psichas A, Morrison DJ, Murphy KG, Zac- Varghese SE, MacDougall K, Preston T, Tedford C, Finlayson GS. loss program. Neuroimage 2012;59:2709–21. Effects of targeted delivery of propionate to the human colon on ap- 34. Burger KS, Stice E. Variability in reward responsivity and obesity: ev- idence from brain imaging studies. Curr Drug Abuse Rev 2011;4:182. petite regulation, body weight maintenance and adiposity in over- 35. Stice E, Burger KS, Yokum S. Reward region responsivity predicts weight adults. Gut 2015;64:1744–54. 13. Psichas A, Sleeth M, Murphy K, Brooks L, Bewick G, Hanyaloglu A, future weight gain and moderating effects of the TaqIA allele. J Neurosci 2015;35:10316–24. Ghatei M, Bloom S, Frost G. The short chain fatty acid propionate 36. Stice E, Spoor S, Bohon C, Small D. Relation between obesity and stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in blunted striatal response to food is moderated by TaqIA A1 allele. rodents. Int J Obes (Lond) 2015;39:424–9. Science 2008;322:449–52. 14. van Bloemendaal L, IJzerman RG, Ten Kulve JS, Barkhof F, Konrad 37. Liou AP, Paziuk M, Luevano J-M, Machineni S, Turnbaugh PJ, Kaplan RJ, Drent ML, Veltman DJ, Diamant M. GLP-1 receptor activation LM. Conserved shifts in the gut microbiota due to gastric bypass re- modulates appetite-and reward-related brain areas in humans. Diabetes duce host weight and adiposity. Sci Trans Med 2013;5:178ra41. 2014;63:4186–96. 38. Carmichael FJ, Israel Y, Crawford M, Minhas K, Saldivia V, Sandrin S, 15. Berthoud H-R. Metabolic and hedonic drives in the neural control of Campisi P, Orrego H. Central nervous system effects of acetate: con- appetite: who is the boss? Curr Opin Neurobiol 2011;21:888–96. tribution to the central effects of ethanol. J Pharmacol Exp Ther 1991; 16. Volkow ND, Wang G-J, Tomasi D, Baler RD. The addictive dimen- sionality of obesity. Biol Psychiatry 2013;73:811–8. 259:403–8. 17. Goldstone AP, Prechtl CG, Scholtz S, Miras AD, Chhina N, Durighel 39. Pedersen C, Lefevre S, Peters V, Patterson M, Ghatei MA, Morgan LM, G, Deliran SS, Beckmann C, Ghatei MA, Ashby DR. Ghrelin mimics Frost GS. Gut hormone release and appetite regulation in healthy non- fasting to enhance human hedonic, orbitofrontal cortex, and hippo- obese participants following oligofructose intake. A dose-escalation study. campal responses to food. Am J Clin Nutr 2014;99:1319–30. Appetite 2013;66:44–53. 14 BYRNE ET AL. 40. Peters SG, Pomare E, Fisher C. Portal and peripheral blood short chain 44. Anil MH, Forbes J. Feeding in sheep during intraportal infusions of fatty acid concentrations after caecal lactulose instillation at surgery. short-chain fatty acids and the effect of liver denervation. J Physiol Gut 1992;33:1249–52. 1980;298:407–14. 41. den Besten G, Lange K, Havinga R, van Dijk TH, Gerding A, van Eunen 45. Anil MH, Forbes J. The roles of hepatic nerves in the reduction of food K, Muller M, Groen AK, Hooiveld GJ, Bakker BM. Gut-derived short- intake as a consequence of intraportal sodium propionate administra- chain fatty acids are vividly assimilated into host carbohydrates and tion in sheep. Q. Q J Exp Physiol 1988;73:539–46. lipids. Am J Physiol Gastrointest Liver Physiol 2013;305:G900–10. 46. De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C, 42. van der Beek CM, Bloemen JG, van den Broek MA, Lenaerts K, Duchampt A, Backhed F, Mithieux G. Microbiota-generated metabo- Venema K, Buurman WA, Dejong CH. Hepatic uptake of rectally ad- lites promote metabolic benefits via gut-brain neural circuits. Cell ministered butyrate prevents an increase in systemic butyrate concen- 2014;156:84–96. trations in humans. J Nutr 2015;145:2019–24. 47. Lal S, Kirkup AJ, Brunsden AM, Thompson DG, Grundy D. Vagal 43. Anastasovska J, Arora T, Canon GJS, Parkinson JR, Touhy K, Gibson afferent responses to fatty acids of different chain length in the rat. Am GR, Nadkarni NA, So PW, Goldstone AP, Thomas EL. Fermentable J Physiol Gastrointest Liver Physiol 2001;281:G907–15. carbohydrate alters hypothalamic neuronal activity and protects against 48. Kentish SJ, Page AJ. The role of gastrointestinal vagal afferent fibres in the obesogenic environment. Obesity (Silver Spring) 2012;20:1016–23. obesity. J Physiol 2015;593:775–86. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The American Journal of Clinical Nutrition Pubmed Central

Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods123

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Abstract

Original Research Communications See corresponding editorial on page 1. Increased colonic propionate reduces anticipatory reward responses in 1–3 the human striatum to high-energy foods 4 4 4 5 8 8 Claire S Byrne, Edward S Chambers, Habeeb Alhabeeb, Navpreet Chhina, Douglas J Morrison, Tom Preston, 9 7 7 7 10 10 Catriona Tedford, Julie Fitzpatrick, Cherag Irani, Albert Busza, Isabel Garcia-Perez, Sofia Fountana, 10 5,6,11 4,11 Elaine Holmes, Anthony P Goldstone, * and Gary S Frost * 4 5 Nutrition and Dietetic Research Group, Division of Diabetes, Endocrinology and Metabolism, Faculty of Medicine, Computational, Cognitive and Clinical 6 7 Neuroimaging Laboratory and Centre for Neuropsychopharmacology, Division of Brain Sciences, and Clinical Imaging Facility, Imperial College London, Hammersmith Hospital, London, United Kingdom; Stable Isotope Biochemistry Laboratory, Scottish Universities Environmental Research Centre, University 9 10 of Glasgow, Glasgow, United Kingdom; School of Science, University of West Scotland, Hamilton, United Kingdom; and Department of Surgery and Cancer, Computational and Systems Medicine, Imperial College London, South Kensington Campus, London, United Kingdom ABSTRACT Keywords: propionate, striatum, reward, fMRI, appetite Background: Short-chain fatty acids (SCFAs), metabolites pro- duced through the microbial fermentation of nondigestible dietary INTRODUCTION components, have key roles in energy homeostasis. Animal research suggests that colon-derived SCFAs modulate feeding behavior via Peripheral signals communicate information about current energy central mechanisms. In humans, increased colonic production of the balance to the brain to maintain energy homeostasis (1). The hedonic SCFA propionate acutely reduces energy intake. However, evidence properties and constant availability of highly palatable energy-dense of an effect of colonic propionate on the human brain or reward- foods promote their overconsumption and weight gain, whereas based eating behavior is currently unavailable. hedonic and reward-based eating behaviors are in turn influenced by Objectives: We investigated the effect of increased colonic propi- peripheral homeostatic signals such as gut hormones (2–4). Hedonic onate production on brain anticipatory reward responses during food responses to food are thought to involve a network of corticolimbic picture evaluation. We hypothesized that elevated colonic propionate brain structures, and are modulated by emotional and cognitive would reduce both reward responses and ad libitum energy intake via factors, as well as sensory cues and anticipated reward. stimulation of anorexigenic gut hormone secretion. Design: In a randomized crossover design, 20 healthy nonobese men This article presents independent research funded by Imperial College (IC) completed a functional magnetic resonance imaging (fMRI) food picture London and supported by the National Institute for Health Research (NIHR) evaluation task after consumption of control inulin or inulin-propionate Clinical Research Facility and Biomedical Research Centre at IC Healthcare NHS Trust. The Section of Endocrinology and Investigative Medicine is ester, a unique dietary compound that selectively augments colonic pro- funded by grants from the Medical Research Council (MRC), Biotechnology pionate production. The blood oxygen level–dependent (BOLD) signal and Biological Sciences Research Council (BBSRC), and NIHR, an Integrative wasmeasuredinapriori brainregions involved in reward processing, Mammalian Biology Capacity Building Award, and an FP7-HEALTH-2009- including the caudate, nucleus accumbens, amygdala, anterior insula, and 241592 EuroCHIP grant, and is supported by the NIHR Biomedical Research orbitofrontal cortex (n = 18 had analyzable fMRI data). Centre Funding Scheme. GSF holds an NIHR Senior Investigator Award, CSB Results: Increasing colonic propionate production reduced BOLD signal and APG are funded by the United Kingdom MRC, and ESC is funded by the during food picture evaluation in the caudate and nucleus accumbens. In BBSRC. This is an open access article distributed under the CC-BY license the caudate, the reduction in BOLD signal was driven specifically by (http://creativecommons.org/licenses/by/3.0/). The views expressed are those of the authors and not necessarily those of a lowering of the response to high-energy food. These central effects IC, the NHS, the NIHR, or the Department of Health. were partnered with a decrease in subjective appeal of high-energy food Supplemental Figures 1–5, Supplemental Tables 1–4, and Supplemental pictures and reduced energy intake during an ad libitum meal. These Methods are available from the “Online Supporting Material” link in the observations were not related to changes in blood peptide YY (PYY), online posting of the article and from the same link in the online table of glucagon-like peptide 1 (GLP-1), glucose, or insulin concentrations. contents at http://ajcn.nutrition.org. Conclusion: Our results suggest that colonic propionate production These authors contributed equally to this work as senior authors. may play an important role in attenuating reward-based eating behavior *To whom correspondence should be addressed. E-mail: tony.goldstone@ via striatal pathways, independent of changes in plasma PYY and GLP-1. imperial.ac.uk (AP Goldstone), g.frost@imperial.ac.uk (GS Frost). This trial was registered at clinicaltrials.gov as NCT00750438. Am J Received December 7, 2015. Accepted for publication April 11, 2016. Clin Nutr 2016;104:5–14. First published online May 11, 2016; doi: 10.3945/ajcn.115.126706. Am J Clin Nutr 2016;104:5–14. Printed in USA. 5 6 BYRNE ET AL. There is increasing evidence that metabolites produced by the Participants colonic microbiota may affect central appetite regulation (5–7). Subjects were recruited via public advertisement and Resistant starch (RS) supplementation alters activation in hy- a healthy volunteer database. Healthy men aged 18–65 y with pothalamic nuclei and gene expression of neuropeptides in- 2 BMI (in kg/m ) 20–35 were eligible for inclusion. Exclusion volved in appetite regulation in rodents (5, 6). The consumption criteria included the following: weight gain or loss .3kgin the of nondigestible carbohydrates (NDCs) also reduces energy in- previous 3 mo, any chronic illness or gastrointestinal disorder, take and weight gain in animal models (8–10). Several physio- history of drug or alcohol abuse in the previous 2 y, use of an- logic benefits associated with the consumption of RS and other tibiotics or medications likely to interfere with energy homeo- NDCs may be mediated through the actions of their fermenta- stasis in the previous 3 mo, claustrophobia, contraindications for tion products, namely, short-chain fatty acids (SCFAs). The MRI scanning, daily smoking, gluten or lactose intolerance, principal SCFAs produced via bacterial fermentation are acetate, consumption of a vegan or vegetarian diet, or depression as propionate, and butyrate, present in the colon in the approximate assessed by a Beck Depression Inventory II score .10 (20). molar ratio of 60:20:20 (11). Our research group demonstrated that increasing circulating acetate directly suppresses appetite Food supplements via central hypothalamic mechanisms in rodents (7). Our recent findings from human studies suggest that propionate may also be IPE designed for targeted delivery of propionate to the colon an important SCFA contributing to appetite regulation (12). The was produced as previously described (12). Inulin was chosen as acute intake of an inulin-propionate ester (IPE), which selec- a control supplement, with the use of the same inulin used to tively increases colonic propionate production, reduced ad prepare both the IPE and control supplements. This controlled for libitum energy intake and increased plasma concentrations of residual fermentation of the backbone NDC. In vitro fermenta- the anorexigenic gut hormones glucagon-like peptide 1 (GLP-1) tions of IPE and inulin suggest comparable increases in acetate and peptide YY (PYY), supporting results of in vitro experi- and butyrate production; thus, any differences in our outcome ments (12, 13). Furthermore, a long-term elevation in colonic measures can be attributed to the preferential increase in pro- propionate production protected against weight gain and re- pionate production with IPE (12). duced hepatic lipid content (12). The exogenous administration of GLP-1 or its analogs and/or Study day protocol PYY reduces brain reward system responses to viewing food pictures in humans (4, 14). However, to date, to our knowledge, Twenty healthy men participated in this randomized, placebo- there are no studies demonstrating an effect of SCFAs on human controlled, within-subject, single-blind crossover study. Subjects brain food-reward responses to influence eating behavior. In the attended 2 separate study visits $6 d apart after an overnight present study, we examined the effect of an acute increase in fast. Subjects were asked to record their dietary intake; avoid colonic propionate production on energy intake and brain regions caffeine, alcohol, and strenuous exercise for 24 h before each involved with reward processing and hedonic eating, includ- visit; and not smoke cigarettes for $48 h before each visit. ing caudate, nucleus accumbens, amygdala, anterior insula, and Study visits were conducted between April and December orbitofrontal cortex (OFC) (15, 16), in healthy nonobese men in 2014 in the National Institute for Health Research/Wellcome a randomized crossover design (Figure 1). We used fMRI to Trust Imperial Clinical Research Facility, Hammersmith Hos- measure activation by the BOLD signal in these regions of in- pital, London, United Kingdom. Weight, height, and body fat terest during an established food evaluation task that used high measurements were collected with the use of bioimpedance energy (HE)– and low energy (LE)–density food pictures (pri- analysis (BC-418 analyzer; Tanita UK). At each visit, subjects mary outcome measure) (3, 17–19). We hypothesized that in- completed a Positive and Negative Affect Schedule to measure creasing colonic propionate production after intake of IPE would mood during the previous week (21). Serial venous blood reduce anticipatory reward responses during evaluation of food samples were collected via a peripheral cannula to assay plasma pictures, a measure of food cue reactivity, compared with control and serum metabolite and hormone concentrations over study inulin via the stimulation of the anorexigenic gut hormones GLP-1 visits (Figure 1). and PYY (4), and would reduce ad libitum energy intake. Breath hydrogen concentration, a marker of colonic fermen- tation (22), was measured with the use of a handheld breath hydrogen analyzer (EC60 Gastrolyser Breath Hydrogen Monitor; Bedfont Scientific), and twelve 100-mm visual analog scales METHODS were completed to assess serial subjective appetite and mood Further details are given in Supplemental Methods. The ratings (Figure 1). study was approved by the West London Research Ethics At 0 min, a standard breakfast containing 10 g IPE (treatment) Committee (08/H0707/99) (NCT00750438). or 10 g inulin (control) was provided to subjects in a randomized order (via sealed envelope). Breakfast was a chocolate milkshake and snack bar (574.5 kcal; 86.4 g carbohydrate, 18.8 g fat, 14.7 g Abbreviations used: AMV, auditory–motor–visual; aROI, anatomical protein, and 3.2 g fiber). Lunch (180 min) was a cheese sandwich region of interest; DRD2, dopamine receptor D2; ED, energy density; EPI, and snack bar (558 kcal; 62.3 g carbohydrate, 24.9 g fat, 21.7 g echoplanar imaging; fROI, functional region of interest; GLP-1, glucagon- protein, and 2.8 g fiber). like peptide 1; HE, high-energy; IPE, inulin-propionate ester; LE, low- At 300 min, subjects completed a 60-min MRI session (Sie- energy; NDC, nondigestible carbohydrate; OFC, orbitofrontal cortex; mens 3T Verio MRI scanner) in the Imperial Clinical Imaging PYY, peptide YY; RS, resistant starch; RYGB, Roux-en-Y gastric bypass; SCFA, short-chain fatty acid. Facility. This time point was chosen based on previous results PROPIONATE AND STRIATAL FOOD REWARD RESPONSES 7 FIGURE 1 Study day protocol. Overview of timings of blood sampling, VAS ratings, breath hydrogen recordings, and scanning protocol. AMV, auditory– motor–visual; IPE, inulin-propionate ester; T1, T1 anatomical scan; VAS, visual analog scale. Adapted from reference 17 with permission. from an acute study that suggest successful delivery of IPE to to ensure exclusion of data for subjects who may not be at- the colon and increased plasma gut hormone concentrations after tending to the task. 240 min (12). AMV control fMRI paradigm Finally, a savory meal of tomato and mozzarella pasta bake (per 100 g: 129 kcal; 17.0 g carbohydrate, 3.9 g fat, 4.8 g protein, An AMV control task was performed to exclude nonspecific and 3.4 g fiber) was served to subjects. Subjects were instructed to changes in the BOLD signal between visits, as previously de- eat until they felt comfortably full. Five of the first 12 subjects scribed (17–19). In a block design, subjects performed 2 of each who completed the study consumed all of the food presented at of the following tasks simultaneously: 1) listening to a story, 2) the meal. As a result, data on food intake for these 5 subjects were tapping their right index finger once every second, or 3) removed from analysis of ad libitum food consumption and the watching a 4-Hz color-flashing checkerboard. amount of food presented to the final 8 subjects was increased. Image processing fMRI scanning protocol fMRI data processing was carried out with the use of FEAT version 6.00, part of FSL (Functional Magnetic Resonance All subjects underwent an MRI scan from 300 to 360 min as Imaging of the Brain (FMRIB) software library; www.fmrib.ox. previously described (17–19). After an initial practice run with ac.uk/fsl), including field map–based EPI unwarping and tem- the use of pictures of animals, subjects had a resting-state fMRI poral derivative and motion variables as covariates in the general scan lasting 10 min followed by the food picture fMRI paradigm linear model, boundary-based registration of EPI to high reso- at 320 min (Figure 1). Subjects had an auditory–motor–visual lution structural space, and nonlinear registration to standard (AMV) fMRI task at 350 min, followed by collection of struc- space. Higher-level analysis used a fixed-effect model to com- tural magnetic resonance brain scans, including high-resolution bine the 2 runs to determine activation for the following contrasts: T1-weighted scans for image registration (Figure 1). Whole- HE food . object, LE food . object, or any food (HE or LE) brain fMRI data were acquired with T2*-weighted gradient- compared with objects. Similar analysis was performed for the echo echoplanar imaging (EPI). single-run AMV paradigm including the onsets of each task (auditory, motor, and visual) to contrast activation during per- Food evaluation fMRI paradigm formance of each task with that when it was not being performed. During the fMRI food picture paradigm, 4 types of color Whole-brain analysis photographs were presented in a block design (6 pictures/block; each image displayed for 2500 ms) split across 2 runs as follows: Whole-brain analysis was performed separately with the use of 1) 60 HE foods (e.g., pizza, cakes, and chocolate), 2)60LE FEAT v6.00 for the HE and LE contrasts with the use of a paired t foods (e.g., salads, vegetables, and fish), 3) 60 non–food-related test to identify regions with significant differences in the BOLD household objects (e.g., furniture and clothing), and 4) 180 signal between control inulin and IPE treatments with the use of blurred images of the other pictures (as a low-level baseline) in both a voxel-wise correction false discovery rate, P , 0.05, and blocks after every food or object block (17–19). While each a cluster-wise correction family-wise error, Z . 2.3, P , 0.05. image was on display in the scanner, subjects were asked to rate simultaneously how appealing each picture was to them with the fMRI regions of interest use of a 5-button hand-held keypad (1 = not at all; 5 = a lot). Exclusion of subjects with a failure to rate .10% of the food Functional regions of interest (fROIs) were determined from and object pictures at either study visit was a predefined cutoff average group activation in a separate cohort of 21 nonobese 8 BYRNE ET AL. TABLE 1 healthy subjects from a previous study (17) for any food (HE or Subject characteristics LE) . object in the nucleus accumbens, amygdala, insula (an- terior), caudate, and OFC brain regions (Supplemental Figure 1 All subjects fMRI analysis and Supplemental Table 1). Similar fROIs were made for the Male 20 (100) 18 (100) AMV control task as follows: superior temporal gyrus posterior European Caucasian 18 (90) 17 (94) division for the secondary auditory cortex; precentral gyrus for Age, y 52 (26, 61) 55 (27, 61) the primary motor cortex; and lingual gyrus for the primary Weight, kg 79.0 6 1.5 78.5 6 1.5 visual cortex (Supplemental Figure 2). An anatomic region of BMI, kg/m 25.2 6 0.5 24.9 6 0.5 interest for the hypothalamus was also generated with the use of Body fat, % 20.6 6 1.1 20.6 6 1.1 the mean of all anatomical T1 scans for the subjects in the BDI-II (maximum 1 (0, 3.3) 1 (0, 3.8) score 63) current study. Time between visits, d 7 (7, 17) 7 (7, 13.3) Values are means 6 SEMs, medians (IQRs), or n (%). Age and an- Comparison of fMRI activation between groups thropometric data are means of first and second study visit measurements. The mean bilateral BOLD signal within each a priori fROI was 2 BDI-II, Beck Depression Inventory II. then extracted for each individual subject for the HE and LE contrasts at each visit to measure differences between treatments. Similar analysis was performed to compare activation in the either inulin or IPE and stayed significantly elevated until the end of the study visit (Figure 2). This suggests that the fermentation relevant fROIs between treatments in the AMV task. of IPE and the release of propionate in the colon occurred in a time course similar to that previously reported (12). As ex- Composite appetite score pected, in a repeated-measures ANOVA, including treatment A composite score was calculated with the use of the following and time as within-subject factors, there was a significant formula (23): [hunger + (100 – fullness) + desire to eat + appetite treatment 3 time interaction in that breath hydrogen concen- for meal] O 4. trations were significantly higher after receiving the control in- ulin than with IPE [F(1, 19) = 3.83, P , 0.01] because of the Blood sample preparation greater amount of fermentable carbohydrate in the control inulin Ten milliliters of blood was collected at each time point for than in the IPE (10 g compared with 7.3 g). assay of plasma glucose (EDTA), serum insulin, and plasma gut hormones (5 mL in lithium heparin tube containing 100 mL Ad libitum energy intake aprotinin protease inhibitor; Nordic Pharma UK). All tubes were centrifuged at 2590 3 g for 10 min at 48C. Samples were sep- Data on energy intake for 5 subjects were removed from arated and frozen at 2208C until analysis. analysis of ad libitum energy intake because these subjects consumed all presented food during one or both visits (see Metabolic and hormone analysis Methods). IPE treatment significantly reduced energy intake by 9.5% 6 5.3% [control 810.4 6 83.4 kcal (95% CI: 631.6, 989.2 Glucose analysis was performed at the Department of Bio- kcal) compared with IPE 711.1 6 79.9 kcal (95% CI: 539.7, chemistry, Hammersmith Hospital, with the use of a ci8200 882.6 kcal), t(14) = 2.41, P = 0.030] (Figure 3). analyzer enzymatic method (Abbott Diagnostics). A human in- sulin radioimmunoassay kit (Millipore) was used for insulin analysis according to manufacturer’s guidelines with 50 mL BOLD signal in food evaluation fMRI task serum. PYY and GLP-1 were measured with the use of previ- ously established in-house specific and sensitive radioimmuno- In 2-factor repeated-measures ANCOVA, including energy assay (24, 25). SCFAs were measured at the Department of density (ED) of food pictures and treatment as within-subject Cancer and Surgery with the use of an Agilent 7000C Triple factors and visit order as a covariate, there was a significant ED 3 Quadrupole GC/MS System according to a previously published treatment interaction for the BOLD signal in the caudate [F(1, method (26). Values are expressed as means 6 SEMs. 16) = 8.86, P = 0.009, Bonferroni correction P = 0.045 for multiple regions of interest] and nucleus accumbens [F(1, 16) = 10.81, P = 0.005, Bonferroni correction P = 0.025] that favored RESULTS HE foods (Figure 4A and B), but not in the amygdala [F(1, 16) Participants = 1.65, P = 0.22], anterior insula [F(1, 16) = 2.65, P = 0.12], or OFC [F(1, 16) = 0.76, P = 0.40] (Figure 4C–E). Subject characteristics are given in Table 1. Two of the 20 In the caudate (Figure 4A), post hoc analysis revealed that IPE men were removed from fMRI analysis because of poor com- treatment significantly reduced the BOLD signal to HE foods pliance with the picture evaluation task (predefined as failure to [effect size: 20.078 6 0.032 (95% CI: 20.147, 20.009), P = rate overall .10% of the food and object pictures during either 0.029] but not to LE foods [effect size: 20.057 6 0.037 (95% study visit), leaving 18 subjects with data for fMRI analysis. CI: 20.134, 0.021), P = 0.14]. However, in post hoc analysis in the nucleus accumbens (Figure 4B), IPE treatment did not sig- Breath hydrogen nificantly reduce the BOLD signal to HE foods [effect size: Breath hydrogen concentrations were significantly elevated 20.082 6 0.055 (95% CI: 20.198, 0.035), P = 0.16] or to LE above baseline concentrations 210 min after subjects received foods [effect size: 20.064 6 0.038 (95% CI: 20.144, 0.016), PROPIONATE AND STRIATAL FOOD REWARD RESPONSES 9 BOLD signal in control fMRI task An AMV control task was performed to look for nonspecific changes in the BOLD signal between treatments, as previously described (17–19). There was no significant difference in the BOLD signal in any fROI between treatments during the control fMRI task (1-factor repeated-measures ANCOVA including visit order as covariate, P = 0.15–0.86; Figure 4F). Food appeal ratings and reaction time In 2-factor repeated-measures ANCOVA, including ED of food pictures and treatment as within-subject factors and visit FIGURE 2 Breath hydrogen concentrations after IPE or control inulin. order as a covariate, there was a significant ED 3 treatment Values are medians (IQRs), n = 20. The dotted vertical line signifies the time interaction for food appeal ratings, with a greater effect for HE point after which .80% IPE previously has been shown to enter the colon foods [F(1, 16) = 5.50, P = 0.032] (Figure 5A). Within HE food (12). Breath hydrogen concentrations after control inulin (y) or IPE (*) compared with baseline concentrations with the use of paired-samples t tests subcategories, there was no significant HE food subcategory 3 ,y ,yyy (calculations performed on normalized data): * P , 0.05, *** P , treatment interaction for food appeal ratings [F(2, 16) = 2.49, 0.005. IPE, inulin-propionate ester; ppm, parts per million. P = 0.099] (Figure 5B). However, independent of HE food sub- category, HE foods were rated significantly less appealing when P = 0.11], although the direction of the IPE effect was similar to patients received IPE than when they received the control [F(1, that for the caudate. 16) = 4.69, P = 0.046] (Figure 5B). By contrast, there was no Independent of ED, there was no significant effect of treatment difference in appeal ratings of object pictures between treat- on the BOLD signal in the amygdala [F(1, 16) = 0.54, P = 0.47], ments when including visit order as a covariate [F(1, 16) = 0.02, anterior insula [F(1, 16) = 0.02, P = 0.89], or OFC [F(1, 16) = P = 0.88]. 1.56, P = 0.23] (Figure 4C–E). There was no significant ED 3 treatment interaction for the There was no significant correlation between the difference in reaction time for subjects to rate the food pictures [F(1, 16) = the BOLD signal to HE foods alone, or any food (HE or LE), in 0.24, P = 0.63] (Figure 5C). However, independent of ED of the caudate (r = 20.11, P = 0.74; and r = 20.41, P = 0.18, food pictures, IPE treatment significantly increased the reaction respectively) or nucleus accumbens (r = 20.19, P = 0.56; and time to food pictures [F(1, 16) = 13.82, P = 0.002] (Figure 5C). r = 20.35, P = 0.27, respectively) between treatments and the Within HE food subcategories, there was no significant HE food difference in energy intake between treatments (n = 13). subcategory 3 treatment interaction for reaction time to food In 2-factor repeated-measures ANCOVA, including ED of food pictures [F(2, 16) = 1.57, P = 0.22] (Figure 5D). However, in- pictures and treatment as within-subject factors and visit order as dependent of HE food subcategory, the reaction time for HE a covariate, there was no significant ED 3 treatment interaction for food pictures was significantly increased after subjects received the BOLD signal in the hypothalamus anatomic region of interest IPE [F(1, 16) = 14.54, P = 0.002] (Figure 5D). By contrast, there [F(1, 16) = 1.61, P = 0.22] (Supplemental Figure 3). Independent was no difference in reaction times for subjects to rate object of ED, there was also no significant effect of treatment on the pictures between treatments when including visit order as a co- BOLD signal in the hypothalamus [F(1, 16) = 1.16, P = 0.30]. variate [F(1, 16) = 2.40] (P = 0.14). In whole-brain analysis, there were no significant regional differences in the BOLD signal for either the HE or LE food Blood hormones and metabolites contrasts surviving correction for multiple comparisons with the use of a voxel-wise false discovery rate of P , 0.05 or a cluster- There was no significant difference in the AUC for 0–360 min wise family-wise error of Z . 2.3, P , 0.05. plasma PYY, GLP-1, or glucose or serum insulin after subjects FIGURE 3 Energy intake at ad libitum meal after IPE or control inulin. Values are mean 6 SEM absolute energy intake after control inulin or IPE (paired-samples t test: *P , 0.05, n = 15) (A) and individual percentage differences in energy intake between IPE and control inulin (B). The horizontal solid line in panel B represents the mean 9.5% reduction in energy intake. IPE, inulin-propionate ester. 10 BYRNE ET AL. FIGURE 4 BOLD signal during food evaluation and AMV control fMRI tasks after consumption of IPE or control inulin. Magnitude of the BOLD signal (percentage) in brain reward systems in the caudate (A), nucleus accumbens (B), anterior insula (C), amygdala (D), and OFC (E) during evaluation of pictures of low-ED foods (minus objects contrast) or high-ED foods (minus objects contrast). Bilateral posterior division of superior temporal gyrus in auditory task, left precentral gyrus in motor task, and bilateral lingual gyrus in visual task after control inulin or IPE, n = 18 (F). Results compared with control inulin with the use of 2-factor (A–E) and 1-factor (F) repeated-measures ANCOVA with a post hoc Fisher least-significant difference test while including visit order as a covariate, *P , 0.05; **P , 0.01. AMV, auditory–motor–visual; ED, energy density; IPE, inulin-propionate ester; OFC, orbitofrontal cortex; preCG, precentral gyrus; postSTG, posterior division of superior temporal gyrus. received IPE compared with control inulin (Supplemental BOLD signal or hedonic response to food pictures, including in Figure 4 and Supplemental Table 2). Furthermore, 2-factor BMI, percentage body fat, mood, total energy intake on the repeated-measures ANOVA revealed no time 3 treatment in- previous day, ratings of nausea, sleepiness, stress or anxiety, or teractions for plasma PYY, GLP-1, or glucose or serum insulin head motion during the fMRI task (Supplemental Table 3). (P = 0.25–0.58). Correlations between outcome measures Serum SCFAs As expected, the change in energy intake between treatments was positively correlated with the change in composite appetite Compared with baseline, there was no significant increase in visual analog scale ratings between treatments (Supplemental serum acetate or propionate concentrations 240 min after subjects Table 4). However, there was no significant correlation between received IPE or control inulin (Table 2). For serum butyrate, elevated colonic propionate on the BOLD signal to HE food in there was a significant increase in concentrations 240 min after the caudate or nucleus accumbens, or in the mean of both re- subjects received both IPE and control inulin compared with gions, and the effect of increased colonic propionate on HE food baseline. There was no difference in SCFA concentrations be- appeal, or in composite appetite visual analog scale ratings tween treatments at baseline (P = 0.25–0.87) or at 240 min (P = (Supplemental Table 4). 0.10–0.88). Confounding variables DISCUSSION There was no significant effect of IPE treatment on composite We used an established fMRI food evaluation paradigm to appetite visual analog scale ratings (Supplemental Figure 5). assess the effects of elevated colonic propionate on brain re- There were no significant differences between treatment visits in sponses during food picture evaluation in a priori regions of potential confounding variables that may have affected the interest previously associated with reward processing and PROPIONATE AND STRIATAL FOOD REWARD RESPONSES 11 FIGURE 5 Food picture appeal ratings and rating reaction times after consumption of IPE or control inulin. Magnitude of appeal ratings (1 = not at all; 5 = a lot) (A and B) and reaction times to rate food pictures of varying energy densities as scored with the use of a hand-held button box (C and D) after control inulin or IPE (n = 18). Results given for low-energy or HE foods (A and C) and different categories of HE foods (chocolate, other sweet, and nonsweet savory) (B and D). Results compared with control inulin with the use of 2-factor repeated-measures ANCOVA with post hoc Fisher least-significant difference test while including visit order as a covariate, *P , 0.05; ***P , 0.005. ED, energy density; HE, high-energy; IPE, inulin-propionate ester. hedonic eating behavior. An acute increase in colonic propionate the ventral striatum BOLD signal during evaluation of HE reduced the BOLD signal during an evaluation of food pictures in compared with LE food pictures, and a preferential reduction in the caudate (dorsal striatum) and nucleus accumbens (ventral the appeal of HE foods, when an fMRI paradigm identical to striatum) in nonobese men, which was greater for HE than for LE that of the current study is used (3). The reduced ventral striatum foods. Indeed, in the caudate, elevated colonic propionate spe- BOLD signal to HE food pictures in the fed compared with cifically reduced the BOLD signal during evaluation of HE but fasted state has also been correlated with a subsequent reduction not LE food pictures. Increased colonic propionate production in ad libitum energy intake (28). Similarly, satiation decreases also reduced the appeal of HE food pictures and prolonged the BOLD responses to food taste in the nucleus accumbens (31), time taken to rate their appeal, an implicit measure that suggested whereas duration of food deprivation correlates with a greater reduced wanting (17, 27). Furthermore, this reduced activation in caudate BOLD signal in response to actual and anticipated re- striatal brain reward systems was accompanied by a reduction in ceipt of palatable food (29). Satiation also decreases regional ad libitum energy intake. This is the first time, to our knowledge, cerebral blood flow at rest, another marker of neuronal activity, that an acute increase in colonic propionate or any other SCFA in the caudate and nucleus accumbens (32). Greater activation in has been shown to significantly reduce anticipatory food hedonic the nucleus accumbens to food pictures is predictive of future responses and associated BOLD signal changes in brain regions snack consumption and reduced weight loss success in an obe- associated with reward processing in humans. sity lifestyle intervention (30, 33). Alterations in caudate acti- Changes in striatal the BOLD signal to food cues previously vation to actual or anticipated receipt of HE palatable food have have been associated with physiologically relevant alterations in been linked to genetic variations in the dopamine receptor D2 food reward processing and eating behavior (3, 28–30). In the (DRD2) gene, which is highly expressed in the striatum and satiated fed compared with fasted state, there is a reduction in linked to increased BMI, familial risk of obesity, and prospective TABLE 2 Serum SCFA concentrations after consumption of IPE or control inulin mmol/L Control inulin IPE D 240 min 3 3 4 0 min 240 min tP 0 min 240 min tP tP Acetate 83.9 6 2.8 96.8 6 7.8 21.72 0.10 86.4 6 4.1 95.4 6 7.2 21.19 0.25 0.49 0.63 Propionate 6.8 6 0.3 7.8 6 0.5 21.64 0.12 7.4 6 0.3 8.3 6 0.5 21.57 0.13 0.16 0.87 Butyrate 5.4 6 0.2 6.1 6 0.3 22.50 0.02 5.3 6 0.2 6.9 6 0.4 23.64 ,0.01 21.87 0.08 Values are means 6 SEMs. n = 20. IPE, inulin-propionate ester; SCFA, short-chain fatty acid. Represents concentrations at 240 min minus baseline values. For 0 min compared with 240 min calculated with the use of paired-samples t tests within each treatment. For D concentrations after control inulin compared with IPE calculated with the use of paired-samples t tests 240 min between treatments. 12 BYRNE ET AL. weight gain (34–36). In addition, after Roux-en-Y gastric bypass bound propionate from IPE is absorbed from the gut and is (RYGB) surgery, obese patients have lower activation in the available systemically (12). The significant increase in butyrate caudate and nucleus accumbens when HE foods are evaluated, observed after both treatments could be explained by the inter- and have lower HE food appeal than patients after gastric banding conversion of acetate to butyrate from microbial fermentation of surgery (18). Acute suppression of plasma PYY and GLP-1 in inulin (41). However, it is unclear why this would be reflected in patients after RYGB surgery increases food reward responses in serum butyrate when splanchnic extraction has been shown to the nucleus accumbens (19). RYGB has been associated with balance gut butyrate production (42). increased colonic propionate production in animal models (37). In addition to reduced striatal responses to food pictures, we This evidence supports a role of the striatum in altered reward observed a 9.5% reduction in energy intake after subjects re- processing and food consumption patterns. It suggests that in- ceived IPE, in line with previous observations (12). However, creased colonic propionate may modulate the engagement of this there was no difference in plasma PYY and GLP-1 concen- brain-reward circuit, resulting in a reduction in energy intake, trations between treatments, a finding that is not in line with our although we could not demonstrate a direct correlation between original hypothesis. It previously has been demonstrated that changes in the BOLD signal and energy intake in our study. an increased intake of NDCs and colonic SCFA production Previous research in animal models supports the role of NDCs can improve body composition and reduce energy intake in- and SCFAs in central appetite regulation. RS supplementation dependent of changes in peripheral gut hormone concentrations reduces activity in hypothalamic appetite regulation centers as in mice (6, 7, 43). This suggests that alternative mechanisms are assessed by manganese-enhanced MRI and stimulates anorexi- responsible for the appetite-regulating effects associated with genic hypothalamic pro-opiomelanocortin expression in rodents the consumption of NDCs and SCFAs, and for the changes in the (5, 6). Acetate itself suppresses appetite via central hypothalamic striatal BOLD signal and food appeal during food picture mechanisms (7) and also has been shown to have other central evaluation in the current study. Propionate is a gluconeogenic effects (38). By contrast, no known studies have investigated the precursor, both at the gut epithelium and liver, and ruminant effect of SCFAs on central appetite regulation in humans. We did studies consistently have demonstrated that an elevated portal not find any significant effect of elevated colonic propionate on concentration of propionate depresses energy intake, which the hypothalamic BOLD signal during food picture evaluation in is abolished with hepatic vagotomy or total hepatic innerva- the current study. However, BOLD imaging in the hypothalamus tion (44, 45). However, we did not identify any difference in has poor reliability related to its small-size, partial-volume effects blood glucose or insulin concentrations between treatments, in because of close proximity to the third ventricle and cerebro- agreement with previous reports (12). Other possible mechanisms spinal fluid spaces, and artifact from the internal carotid artery. driving our observations may be via the induction of vagal Furthermore, an interpretation of changes in the overall BOLD signaling in the gut or portal vein through stimulation of free fatty signal in the hypothalamus may be complicated by the multiple acid receptor 3 (46–48). Further work is needed to gain a better smaller hypothalamic nuclei containing both orexigenic and understanding of the gut–liver–brain signaling pathways in re- anorexigenic feeding neurons. sponse to increased colonic propionate. This would provide in- One of the major limitations of NDC supplementation is that formation about whether our observations are a direct effect of large doses are needed to observe effects that are in line with propionate on neural pathways or a secondary response mech- those noted in animal studies. For example, our research group anism to propionate metabolism. previously has shown that .35 g NDC/d is needed to suppress We believe the major strengths of our study are the following: 1) appetite and stimulate an increase in plasma PYY concentrations the use of fMRI, a well-validated noninvasive measure of human (39). However, the development of IPE uniquely allows for the brain activity; 2) the incorporation of a well-established food targeted delivery of a known amount of propionate directly to evaluation paradigm that is sensitive to peripheral signals the colon, which normally only would be obtained from a high- influencing appetite and reward-based eating behavior, such as fiber diet, without the associated gastrointestinal side effects gut hormones and after bariatric surgery (17–19); 3) the exclu- (e.g., abdominal bloating or flatulence). We have previously sion of nonspecific effects on the BOLD signal with the use of shown with the use of a C-labeled variant of IPE that .80% of a control fMRI task; and 4) the within-subject crossover design. the bound propionate is released coincident with breath hydro- A limitation of our study is the lack of energy intake data for 5 gen. This suggests delivery of the majority of bound propionate subjects, which may have reduced the ability to detect correla- to the colon (12). We estimate that a 10-g dose of IPE delivers tions between outcome measures. Another limitation was the 2.36 g propionate to the colon, which is 2.5 times habitual daily inclusion of only a nonobese male cohort. The findings will need propionate production. In the current study, the breath hydrogen confirmation in an obese cohort and in women, who may have data suggests significant fermentation by 210 min and at the altered reward and emotional responses to food. The effect of time of the MRI session. Despite this, we were unable to detect long-term IPE supplementation on striatal reward responses also any difference in serum propionate between treatments. Our remains to be elucidated. current measurement may have lacked sensitivity to record In conclusion, elevated colonic propionate significantly re- minor increases in peripheral circulatory propionate, particularly duced the striatal BOLD signal during evaluation of HE foods, when measured at a single postprandial time point. This is un- reduced HE food picture appeal, and reduced energy intake at an surprising, because .95% propionate present in the portal vein ad libitum meal in nonobese men, an effect that was independent is extracted by the liver, resulting in only a minor fraction of changes in plasma PYY, GLP-1, and glucose and serum in- reaching the peripheral circulation (40). Nevertheless, we have sulin. These results suggest that colonic propionate may play an previously demonstrated a significant increase in propionate C important role in human appetitive and reward-based eating enrichment in the peripheral circulation, revealing that the behavior at least in part through brain striatal pathways. PROPIONATE AND STRIATAL FOOD REWARD RESPONSES 13 We thank Tom Clarkson for the synthesis of the inulin-propionate ester and 18. Scholtz S, Miras AD, Chhina N, Prechtl CG, Sleeth ML, Daud NM, Milena Rundle, Amin Alamshah, Katerina Petropoulou, and Annette Henry Ismail NA, Durighel G, Ahmed AR, Olbers T. Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than for their assistance with the radioimmunoassay. after gastric banding. Gut 2014;63:891–902. The authors’ responsibilities were as follows—APG and GSF: designed 19. Goldstone AP, Miras AD, Scholtz S, Jackson S, Neff KJ, Pénicaud the study; CSB, ESC, and HA: recruited the subjects; DJM, TP, and CT: L, Geoghegan J, Chhina N, Durighel G, Bell JD. Link between in- provided the materials; CSB, ESC, HA, NC, JF, CI, and AB: collected the creased satiety gut hormones and reduced food reward following data; CSB, ESC, APG, and GSF: analyzed the data; CSB, ESC, DJM, IG-P, gastric bypass surgery for obesity. J Clin Endocrinol Metab 2016; SF, EH, APG, and GSF: interpreted the data and wrote the manuscript; and 101: 599–609. all authors: read and approved the final manuscript. A patent application for 20. Beck AT, Steer RA, Ball R, Ranieri WF. Comparison of Beck De- “Compounds and their effects on appetite control and insulin sensitivity” pression Inventories-IA and-II in psychiatric outpatients. J Pers Assess surrounding the use of inulin-propionate ester has been filed by DJM and 1996;67:588–97. 21. Killgore WD, Yurgelun-Todd DA. Affect modulates appetite-related GSF (WO2014020344). None of the other authors reported a conflict of brain activity to images of food. Int J Eat Disord 2006;39:357–63. interest related to the study. 22. Levitt MD. Production and excretion of hydrogen gas in man. N Engl J Med 1969;281:122–7. 23. Woodend DM, Anderson GH. Effect of sucrose and safflower oil preloads on short term appetite and food intake of young men. Appetite REFERENCES 2001;37:185–95. 1. Murphy KG, Bloom SR. Gut hormones and the regulation of energy 24. Adrian TE, Ferri G, Bacarese-Hamilton A, Fuessl H, Polak J, Bloom S. homeostasis. Nature 2006;444:854–9. Human distribution and release of a putative new gut hormone, peptide 2. Dagher A. Functional brain imaging of appetite. Trends Endocrinol YY. Gastroenterology 1985;89:1070–7. Metab 2012;23:250–60. 25. Kreymann B, Ghatei M, Williams G, Bloom S. Glucagon-like peptide- 3. Goldstone AP, Prechtl de Hernandez CG, Beaver JD, Muhammed K, 1 7-36: a physiological incretin in man. Lancet 1987;2:1300–4. Croese C, Bell G, Durighel G, Hughes E, Waldman AD, Frost G. 26. Moreau NM, Goupry S, Antignac J, Monteau F, Le Bizec B, Champ Fasting biases brain reward systems towards high-calorie foods. Eur J M, Martin L, Dumon H. Simultaneous measurement of plasma con- Neurosci 2009;30:1625–35. centrations and 13 C-enrichment of short-chain fatty acids, lactic acid 4. De Silva A, Salem V, Long CJ, Makwana A, Newbould RD, Rabiner EA, and ketone bodies by gas chromatography coupled to mass spec- Ghatei MA, Bloom SR, Matthews PM, Beaver JD. The gut hormones trometry. J Chromatogr B Analyt Technol Biomed Life Sci 2003;784: PYY 3-36 and GLP-1 7-36 amide reduce food intake and modulate brain 395–403. activity in appetite centers in humans. Cell Metab 2011;14:700–6. 27. Finlayson G, King N, Blundell J. The role of implicit wanting in re- 5. Shen L, Keenan MJ, Martin RJ, Tulley RT, Raggio AM, McCutcheon lation to explicit liking and wanting for food: implications for appetite KL, Zhou J. Dietary resistant starch increases hypothalamic POMC control. Appetite 2008;50:120–7. expression in rats. Obesity (Silver Spring) 2009;17:40–5. 28. Fletcher PC, Napolitano A, Skeggs A, Miller SR, Delafont B, Cam- 6. So P-W, Yu W-S, Kuo Y-T, Wasserfall C, Goldstone AP, Bell JD, Frost bridge VC, de Wit S, Nathan PJ, Brooke A, O’Rahilly S. Distinct G. Impact of resistant starch on body fat patterning and central appetite modulatory effects of satiety and sibutramine on brain responses to regulation. PLoS One 2007;2:e1309. food images in humans: a double dissociation across hypothalamus, 7. Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L, amygdala, and ventral striatum. J Neurosci 2010;30:14346–55. Anastasovska J, Ghourab S, Hankir M, Zhang S. The short-chain fatty 29. Stice E, Burger K, Yokum S. Caloric deprivation increases responsivity acid acetate reduces appetite via a central homeostatic mechanism. Nat of attention and reward brain regions to intake, anticipated intake, and Commun 2014;5:3611. images of palatable foods. Neuroimage 2013;67:322–30. 8. Cani PD, Neyrinck AM, Maton N, Delzenne NM. Oligofructose pro- 30. Lawrence NS, Hinton EC, Parkinson JA, Lawrence AD. Nucleus motes satiety in rats fed a high-fat diet: involvement of glucagon-like accumbens response to food cues predicts subsequent snack con- peptide-1. Obes Res 2005;13:1000–7. sumption in women and increased body mass index in those with re- 9. Delmée E, Cani PD, Gual G, Knauf C, Burcelin R, Maton N, Delzenne duced self-control. Neuroimage 2012;63:415–22. NM. Relation between colonic proglucagon expression and metabolic re- 31. Thomas JM, Higgs S, Dourish CT, Hansen PC, Harmer CJ, McCabe C. sponse to oligofructose in high fat diet-fed mice. Life Sci 2006;79:1007–13. Satiation attenuates BOLD activity in brain regions involved in reward 10. Arora T, Loo RL, Anastasovska J, Gibson GR, Tuohy KM, Sharma RK, and increases activity in dorsolateral prefrontal cortex: an fMRI study Swann JR, Deaville ER, Sleeth ML, Thomas EL. Differential effects of in healthy volunteers. Am J Clin Nutr 2015;101:697–704. two fermentable carbohydrates on central appetite regulation and body 32. Gautier JF, Parigi A, Chen K, Salbe AD, Bandy D, Pratley RE, composition. PLoS One 2012;7:e43263. Ravussin E, Reiman EM, Tataranni PA. Effect of satiation on brain 11. Cummings JH, Pomare E, Branch W, Naylor C, Macfarlane G. Short activity in obese and lean women. Obes Res 2001;9:676–84. chain fatty acids in human large intestine, portal, hepatic and venous 33. Murdaugh DL, Cox JE, Cook EW, Weller RE. fMRI reactivity to high- blood. Gut 1987;28:1221–7. calorie food pictures predicts short-and long-term outcome in a weight- 12. Chambers ES, Viardot A, Psichas A, Morrison DJ, Murphy KG, Zac- Varghese SE, MacDougall K, Preston T, Tedford C, Finlayson GS. loss program. Neuroimage 2012;59:2709–21. Effects of targeted delivery of propionate to the human colon on ap- 34. Burger KS, Stice E. Variability in reward responsivity and obesity: ev- idence from brain imaging studies. Curr Drug Abuse Rev 2011;4:182. petite regulation, body weight maintenance and adiposity in over- 35. Stice E, Burger KS, Yokum S. Reward region responsivity predicts weight adults. Gut 2015;64:1744–54. 13. Psichas A, Sleeth M, Murphy K, Brooks L, Bewick G, Hanyaloglu A, future weight gain and moderating effects of the TaqIA allele. J Neurosci 2015;35:10316–24. Ghatei M, Bloom S, Frost G. The short chain fatty acid propionate 36. Stice E, Spoor S, Bohon C, Small D. Relation between obesity and stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in blunted striatal response to food is moderated by TaqIA A1 allele. rodents. Int J Obes (Lond) 2015;39:424–9. Science 2008;322:449–52. 14. van Bloemendaal L, IJzerman RG, Ten Kulve JS, Barkhof F, Konrad 37. Liou AP, Paziuk M, Luevano J-M, Machineni S, Turnbaugh PJ, Kaplan RJ, Drent ML, Veltman DJ, Diamant M. GLP-1 receptor activation LM. Conserved shifts in the gut microbiota due to gastric bypass re- modulates appetite-and reward-related brain areas in humans. Diabetes duce host weight and adiposity. Sci Trans Med 2013;5:178ra41. 2014;63:4186–96. 38. Carmichael FJ, Israel Y, Crawford M, Minhas K, Saldivia V, Sandrin S, 15. Berthoud H-R. Metabolic and hedonic drives in the neural control of Campisi P, Orrego H. Central nervous system effects of acetate: con- appetite: who is the boss? Curr Opin Neurobiol 2011;21:888–96. tribution to the central effects of ethanol. J Pharmacol Exp Ther 1991; 16. Volkow ND, Wang G-J, Tomasi D, Baler RD. The addictive dimen- sionality of obesity. Biol Psychiatry 2013;73:811–8. 259:403–8. 17. Goldstone AP, Prechtl CG, Scholtz S, Miras AD, Chhina N, Durighel 39. Pedersen C, Lefevre S, Peters V, Patterson M, Ghatei MA, Morgan LM, G, Deliran SS, Beckmann C, Ghatei MA, Ashby DR. Ghrelin mimics Frost GS. Gut hormone release and appetite regulation in healthy non- fasting to enhance human hedonic, orbitofrontal cortex, and hippo- obese participants following oligofructose intake. A dose-escalation study. campal responses to food. Am J Clin Nutr 2014;99:1319–30. Appetite 2013;66:44–53. 14 BYRNE ET AL. 40. Peters SG, Pomare E, Fisher C. Portal and peripheral blood short chain 44. Anil MH, Forbes J. Feeding in sheep during intraportal infusions of fatty acid concentrations after caecal lactulose instillation at surgery. short-chain fatty acids and the effect of liver denervation. J Physiol Gut 1992;33:1249–52. 1980;298:407–14. 41. den Besten G, Lange K, Havinga R, van Dijk TH, Gerding A, van Eunen 45. Anil MH, Forbes J. The roles of hepatic nerves in the reduction of food K, Muller M, Groen AK, Hooiveld GJ, Bakker BM. Gut-derived short- intake as a consequence of intraportal sodium propionate administra- chain fatty acids are vividly assimilated into host carbohydrates and tion in sheep. Q. Q J Exp Physiol 1988;73:539–46. lipids. Am J Physiol Gastrointest Liver Physiol 2013;305:G900–10. 46. De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C, 42. van der Beek CM, Bloemen JG, van den Broek MA, Lenaerts K, Duchampt A, Backhed F, Mithieux G. Microbiota-generated metabo- Venema K, Buurman WA, Dejong CH. Hepatic uptake of rectally ad- lites promote metabolic benefits via gut-brain neural circuits. Cell ministered butyrate prevents an increase in systemic butyrate concen- 2014;156:84–96. trations in humans. J Nutr 2015;145:2019–24. 47. Lal S, Kirkup AJ, Brunsden AM, Thompson DG, Grundy D. Vagal 43. Anastasovska J, Arora T, Canon GJS, Parkinson JR, Touhy K, Gibson afferent responses to fatty acids of different chain length in the rat. Am GR, Nadkarni NA, So PW, Goldstone AP, Thomas EL. Fermentable J Physiol Gastrointest Liver Physiol 2001;281:G907–15. carbohydrate alters hypothalamic neuronal activity and protects against 48. Kentish SJ, Page AJ. The role of gastrointestinal vagal afferent fibres in the obesogenic environment. Obesity (Silver Spring) 2012;20:1016–23. obesity. J Physiol 2015;593:775–86.

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The American Journal of Clinical Nutrition – Pubmed Central

Published: May 11, 2016

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