# Orosensory perception of fat/sweet stimuli and appetite-regulating peptides before and after sleeve gastrectomy or gastric by-pass in adult women with obesity

Arnaud Bernard, Johanne Le Beyec-Le Bihan, Loredana Radoi, Muriel Coupaye, Ouidad Sami, Nathalie Casanova, Cedric Le May, Xavier Collet, Pascaline Delaby, Cindy Le Bourgot, et al.

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Arnaud Bernard, Johanne Le Beyec-Le Bihan, Loredana Radoi, Muriel Coupaye, Ouidad Sami, et al. Orosensory perception of fat/sweet stimuli and appetite-regulating peptides before and after sleeve gastrectomy or gastric by-pass in adult women with obesity. Nutrients, 2021, 13 (3), pp.878-10.3390/nu13030878. [hal-03170655](https://hal.science/hal-03170655)

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# Orosensory perception of fat/sweet stimuli and appetite-regulating peptides before and after sleeve gastrectomy or gastric by-pass in adult women with obesity.

Arnaud Bernard¹, Johanne Le Beyec-Le Bihan²,³, Loredana Radoi⁴, Muriel Coupaye⁵, Ouidad Sami⁵, Nathalie Casanova⁵, Cédric Le May⁶, Xavier Collet⁷, Pascaline Delaby⁸, Cindy Le Bourgot⁹, Philippe Besnard¹* and Séverine Ledoux³,⁵*

**Citation:** Bernard, A; Le Beyec-Le-Bihan, J; Radoi, L; Coupaye, M; Sami, O; Casanova, N; Collet, X; Delaby, P; Le Bourgot, C; Besnard, P; Ledoux, S. Orosensory perception of fat/sweet stimuli and appetite regulating peptides before and after sleeve gastrectomy or gastric by-pass in adult obese women. *Nutrients* **2021**, *12*, x.
https://doi.org/10.3390/xxxxx

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¹ UMR Lipides/Nutrition/Cancer 1231 INSERM /Univ Bourgogne-Franche Comté/ AgroSup Dijon, 21000 Dijon, France.

² UF de Génétique de l'Obésité et des Dyslipidémies, Service de Biochimie Endocrinienne et Oncologique, Centre de Génétique Moléculaire et Chromosomique, Groupe Hospitalier Pitié-Salpêtrière (APHP), 75013 Paris, France.

³ Fonctions Gastro-Intestinales, Métaboliques et Physiopathologies Nutritionnelles
Inserm UMR1149, Centre de Recherche sur l'Inflammation Paris Montmartre, 75890 Paris Cedex 18, France.

⁴ Service d'odontologie, Hôpital Louis Mourier (APHP), 92700 Colombes, France.

⁵ Explorations Fonctionnelles, Hôpital Louis Mourier (APHP), 92700 Colombes and Université de Paris, France.

⁶ UMR 1087 INSERM/6291 CNRS, 44007 Nantes, France.

⁷ UMR 1048 INSERM/Toulouse III, 31400 Toulouse, France.

⁸ Lesieur groupe Avril, 92600 Asnières-sur-Seine, France.

⁹ Tereos, 77230 Moussy-le-Vieux, France.

* Correspondence: P Besnard, Physiologie de la Nutrition, UMR 1231 Lipides/Nutrition/Cancer, AgroSup Dijon, 26, Bd Dr Petitjean, F-21000 Dijon, France. e-mail: pbesnard@u-bourgogne.fr and/or S. Ledoux, Explorations Fonctionnelles, Hôpital Louis Mourier, 178 rue des Renouillers, F-92700 Colombes, France. e-mail: severine.ledoux@lmr.aphp.fr

**Short title:** Gustation and bariatric surgery

**ABSTRACT:** The aim of this study was to explore the impact of bariatric surgery on the fat and sweet taste perception and to determine the possible correlations with gut appetite-regulating peptides and subjective food sensations. Women with a severe obesity (BMI> 35 kg/m²) were studied 2 weeks before and 6 months after a vertical sleeve gastrectomy (VSG, n=32) or a Roux-en-Y gastric by-pass (RYGB, n=12). Linoleic acid (LA) and sucrose perception thresholds were determined using the three alternative-forced choice procedure, gut hormones were assayed before and after a test meal and subjective changes in oral food sensations were self-reported using a standardized questionnaire. Despite a global positive effect of both surgeries on the reported gustatory sensations, a change in the taste sensitivity was only found after RYGB for LA. However, the fat and sweet taste perceptions were not homogenous between patients undergone the same surgery procedure, suggesting the existence of 2 subgroups: patients with and without taste improvement. These gustatory changes were not correlated to the surgery-mediated modifications of the main gut appetite-regulating hormones. Collectively these data highlight the complexity of relationships between bariatric surgery and taste sensitivity and suggest that VSG and RYGB might impact differentially the fatty taste perception.

**Keywords:** Fat taste; sweet taste; obesity; bariatric surgery; appetite-regulating hormones; health

## 1. Introduction

Ubiquitous availability of tasty energy-dense foods rich in fat and sugar is thought to play a significant role in the obesity prevalence worldwide [1]. Interestingly, a preferential consumption of highly palatable foods (i.e. pleasant in the mouth) is often observed
in obese subjects [2-4] suggesting that the perception of orosensory sensations in response to fat and sweet stimuli might be compromised in obesity leading to unhealthy food choices.

Bariatric surgery is the most efficient method to reduce severe obesity and improve associated comorbidities (e.g. type-2 diabetes). To date, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are commonly performed procedures by reason of their long-term effectiveness [5], despite important anatomic differences [6]. Paradoxically, how these surgery procedures work is not yet fully understood likely due to the complexity of induced homeostatic changes. For example, the beneficial effect of RYGB on the remission of type-2 diabetes appears to be not fully attributable to the weight loss, as previously expected [7,8].

Gustation, known to be a key determinant for food selection, is a complex phenomenon including the oral detection of sensory inputs, central identification of tastants, evaluation of their intensity and generation of hedonic adaptations contributing to the decision to eat or not [9]. A growing number of studies suggests that the taste perception might be affected by bariatric surgery [10-12]. Nevertheless, whether bariatric surgery-induced changes of the gustatory sensitivity is a plausible contributor to a successful weight loss is still elusive. Indeed, the analysis of both subjective orosensory sensations and ingestive behavior after bariatric surgery usually shows an improvement of the orosensory perception of fat and sweet stimuli associated with a decreased interest for and intake of high caloric foods [12]. However, the fact that these data are generated by using indirect methods (e.g. self-reported questionnaires) limits their physiological relevance [12]. Although direct sensory methods (e.g. alternative force-choice tests, taste strips) were used to explore the changes of gustatory sensitivity (mainly sweet taste) in patients with obesity, they led to discrepant results, some studies reporting a lower sweet threshold after surgery (i.e. a better sensitivity), [13-15], while others showed no change [16-21]. Moreover, despite of the well-known high palatability, and in turn attractiveness, of fat-rich foods [22], we don't know whether the fat taste sensitivity is modified after bariatric surgery and what is the respective impact of RYGB and VSG procedures on this sensory parameter. Finally, the fact that RYGB and VSG differentially alter the secretion pattern of appetite-regulating peptides (i.e. insulin, GLP-1, PYY and ghrelin) [23], known to be involved in modulating taste perception [24], raises an additive question: Does the global change of gut hormone balance induced by the bariatric surgery affect the fatty and sweet taste sensitivity?

To explore these issues, oral perception thresholds in response to fat and sweet stimuli, subjective changes of food sensations and post-prandial levels of appetite-regulating hormones were analyzed before and 6 months after VSG or RYGB surgery in adult women suffering of a severe obesity.

## 2. Subjects and Methods

### 2.1. Subjects

This clinical study was approved by french ethics committees (Comité de Protection des Personnes, CPP n° 15-032 and Agence Nationale de la Sécurité des Médicaments, ANSM n° 150811B-21) and was registered at Clinical Trials (NCT#02497274). Severe obese (BMI ≥ 35 kg/m²) adult (≥18 and ≤55y-old, mean age = 38.4±1.3y ) patients candidate for bariatric surgery were selected according to the following exclusion criteria: medications known to alter the taste, buccal decays, previous surgical treatment of obesity, diabetes (hypoglycemic drug intake or fasted plasma glucose level >7 mmol/L), chronic inflammatory diseases and tobacco use. All subjects received detailed information about the study and provided a written consent. To avoid gender-mediated bias [25], this study was conducted in women only.

On the 53 subjects initially included, 9 subjects were secondary excluded: 3 were not operated, 5 have withdrawn their consent due to constraints of repetitive visits and 1 for a chronic oral inflammation (Fig. 1-A). Among the 44 selected patients, 32 underwent a VSG procedure and 12 a RYGB one. All the interventions were performed
laparoscopically, as previously described [26], with a 150 cm alimentary limb and a 60 cm biliopancreatic limb for RYGB according to international recommendations [27]. Pre- and post-operative multidisciplinary managements were performed in the Louis Mourier Hospital (Assistance Publique Hôpitaux de Paris - APHP) and were previously described elsewhere [28].

Since the lipid perception threshold appears to be unrelated to BMI in human [29] and to be consistent with the post-surgery timing of previous studies [14-16,19,30], while limiting the risk of patients leaving the study, the post-operative time period chosen in this protocol was 6 months. Each patient was subjected to a set of 3 successive sessions before (S1 to S3) and 6 months after (S4 to S6) surgery (Fig. 1-B). Sessions 1 and 4 (S1/S4) included a dietary habit questionnaire (4-day food recall), a blood collection and an analysis of the body composition including body fat mass by multifrequency impedancemetry (Secca, France). A questionnaire on the taste and olfaction changes (TOC) [31], adapted to include questions about fat-mediated sensations, was added to the S4 (i.e. the first post-operative session). An analogic scale scored from 1 (no change) to 10 (maximal change) was used to evaluate the subjective gustatory and olfactory changes. Determination of fat and sweet taste changes was performed by using the 3-alternative force choice procedure (3-AFC) [32] during the sessions S2/S3 and S5/S6, respectively.

<figure><img src="image_3.png" /><figcaption>Fig. 1</figcaption></figure>

**Figure 1.** Cohort composition and study design. A- From 53 patients initially selected, 44 were included, 32 undergone a vertical sleeve gastrectomy (VSG) and 12 a Roux-en-Y gastric by-pass (RYGB). B- Before surgery, patients were subjected to 3 successive sessions (S1-S3) including a clinical exploration and the determination of sucrose and linoleic acid (LA) perception thresholds. The same exploratory design was done 6 months after surgery.

## 2.2. 3-alternative force choice tests

LA and sucrose were used to evaluate the fat and sweet taste, respectively. LA was chosen because this polyunsaturated fatty acid, widely found in foods, binds with a high
affinity the lipid-receptors expressed in the taste buds (i.e. CD36 and GPR120) [24]. To reduce the potential nutritional interferences on the taste function due to food intake, all subjects were asked to eat the evening before the 3-AFC sessions, the following standardized meal: raw tomato (100g) + 1 teaspoon of sunflower oil (5g), bread (20g of french baguette), chicken breast (120g), potatoes cooked in water (250g), green beans (100g), butter (5g), 1 yoghurt sweetened with cane sugar, 1 standard apple compote).

LA and sucrose thresholds were determined at 9 AM in fasting patients. In brief, subjects were asked to identify the sample that is different from the 2 others. Sets were presented in an ascending concentration from 0.00028% to 5% LA (wt/wt) spaced by 0.25 log units (18 solutions in total) and from 0.2 to 1.6% sucrose with an increment of 0.2% at each step (8 solutions in total). The procedure was stopped when the experimental sample was correctly identified 3 times, consecutively. This concentration represented the detection threshold value of the subject. Samples of 5 ml were tested at room temperature. Subjects were instructed to hold the sample in their mouth for 7 s, spit the solution out, and wait for 20 s before tasting the next sample. The interval between 2 sets was 60–120 s, during which participants were asked to rinse their mouth with water. To limit both visual and olfactory interferences, the samples were presented in opaque cups and participants weared a nose clip.

## 2.3. Preparation of linoleic acid samples for 3-AFC tests

The protocol used to prepare LA samples is fully detailed elsewhere [33]. In brief, LA (Sigma Aldrich) emulsions were prepared in a water solution containing 5% acacia gum (wt/wt; Merck), 5% mineral oil (wt/wt; Cooper), and 0.01% EDTA (wt/wt; VWR international). According to [32], acacia gum and mineral oil were added to limit viscosity and lubricity differences between control and experimental samples and EDTA was added to prevent the oxidation of LA. Samples were mixed conventionally by using a stirrer (Corning) and emulsified with a sonicator (Misonix sonicator model S-4000; QSonica LLC). The duration of the sonication was adapted to LA concentrations to obtain a similar particle size in order to minimize textural influences [33]. In all cases, sonication was conducted by lapses of 30 s separated by a 1-min pause. Sonication was conducted in a hermetic chamber saturated with nitrogen gas, using an ice bath and a temperature-controlled sonicator in order to limit the formation of oxidized compounds during the preparation of the emulsions.

## 2.4. Hormonal assessments

Plasma insulin (LiaisonXL®, Diasorin, France), glucagon-like-peptide-1 (GLP-1) (EDI™ Total GLP-1 ELISA Kit - Epitope Diagnostics, eurobio, France), peptide YY (PYY) and total ghrelin (U-PLEX Metabolic Human assay, Meso Scale Discovery, USA) were assessed before (t=0), 30 and 90 min after a test meal (Fresubin 2 kcal Drink®: 200 ml containing 400 Kcal, carbohydrates 35 g, lipids 20 g, protein 20 g). For GLP-1, blood collection was done in presence of DPP4 inhibitor.

## 2.5. Statistics

Results are expressed as means ± SD. Data were analyzed with GraphPad Prism software (V7.01, Graphpad software inc.) and sigmaplot. Thresholds data were analyzed with a paired Wilcoxon test with the Pratt's method. Contingency data were analyzed with the X²-Fisher exact test. For the other data, after verification of the distribution normality they were analyzed using the Student t-test or the Mann-Whitney test with or without pairing. Correlations between the perception thresholds and hormonal concentrations were analyzed using Spearman's correlations.

The principal component analysis (PCA) was done with R (v4.0.2; The R Foundation) software and the mixOmics package (v6.12.2) [34]. The purpose of this multivariate analysis was to explore whether the global changes in the satiety-regulating hormones from digestive tract elicited by surgery were sufficient to segregate patients having undergone a VSG from those with a RYGB and to distinguish patients displaying a gustatory
improvement from those not improved. In brief, the PCA is used to identify the principle sources of variations that are able to describe the different groups. The first component of the PCA explains the most of the variability (x-axis), the following components explains the remaining variability (y-axis).

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## 2.6. Power analysis

To our knowledge, exploration of the oral perception thresholds of lipid stimuli before and after VSG or RYGB surgery had never been performed when this study has been undertaken. Therefore, our study size (i.e. ≥10 patients by surgery) was deduced from previously published data on the effects of VSG and RYGB on the perception thresholds of various tastants including sucrose [14,16]. This sample size seems to be a reasonable extrapolation especially due to the fact that each patient being his own-control leads to a reduction of the data variability.

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# 3. Results

## 3.1. Changes of the body composition and food intake after VSG or RYGB.

A similar decrease in the body mass and fat mass was found 6 months after surgery whatever the procedure used (Table 1). Daily energy intake was also reduced in a same proportion after the two types of surgery (-46.6% and 41.6% after VSG and RYGB, respectively). While the daily carbohydrate and protein intakes were overall similar whatever the surgery procedure, lipids consumption was slightly lower in the RYGB group than in the VSG patients (Table 2).

<table><caption>Table 1. Body composition before (pre-op) and 6 months (post-op) after surgery</caption><thead><tr><th>Variables</th><th>VSG (n=32)</th><th>RYGB (n=12)</th><th>P-value post-op (VSG vs RYGB)</th></tr></thead><tbody><tr><td>Body mass (kg)</td><td></td><td></td><td></td></tr><tr><td>Pre-op</td><td>115.8 ±2.3 ] ***</td><td>111.7 ±3.8 ] ***</td><td>ns</td></tr><tr><td>Post-op</td><td>85.2 ±2.1 ] ***</td><td>85.4 ±3.0 ] ***</td><td>ns</td></tr><tr><td>Weight loss (kg)</td><td>30.5 ±1.2</td><td>26.2 ±1.7</td><td>0.06</td></tr><tr><td>Weight loss (%)</td><td>26.4 ±1.0</td><td>23.3 ±1.2</td><td>ns</td></tr><tr><td>BMI (kg/m²)</td><td></td><td></td><td></td></tr><tr><td>Pre-op</td><td>43.1 ±0.7 ] ***</td><td>42.3 ±1.0 ] ***</td><td>ns</td></tr><tr><td>Post-op</td><td>31.6 ±0.6 ] ***</td><td>32.1 ±0.9 ] ***</td><td>ns</td></tr><tr><td>Fat mass (% BM)</td><td></td><td></td><td></td></tr><tr><td>Pre-op</td><td>51.6 ±0.5 ] ***</td><td>51.2 ±0.9 ] ***</td><td>ns</td></tr><tr><td>Post-op</td><td>43.3 ±1.0 ] ***</td><td>43.9 ±1.2 ] ***</td><td>ns</td></tr></tbody></table>

Means ± SD; **, p<0.001; ns, not significant.
Pre-op vs Post-op, paired Student; VSG vs RYGB, Student. Op, operated.

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<table><caption>Table 2. Reported food intake (4-days food recall) before (pre-op) and 6 months (post-op) after surgery</caption><thead><tr><th>Variables</th><th>VSG (n=32)</th><th>RYGB (n=12)</th><th>P-value post-op (VSG vs RYGB)</th></tr></thead><tbody><tr><td>Food intake (g/d)</td><td></td><td></td><td></td></tr><tr><td>Pre-op</td><td>1173.0±39.9 ] ***</td><td>1083.0±90.8 ] **</td><td>*</td></tr><tr><td>Post-op</td><td>568.7±35.5 ] ***</td><td>707.3±64.4 ] **</td><td></td></tr><tr><td>Energy intake (Kcal/d)</td><td></td><td></td><td></td></tr><tr><td>Pre-op</td><td>1564.5±48.8 ] ***</td><td>1557.3±90.1 ] ***</td><td>ns</td></tr><tr><td>Post-op</td><td>835.5±44.3 ] ***</td><td>908.2±61.0 ] ***</td><td></td></tr><tr><td>Carbohydrates (% energy intake)</td><td></td><td></td><td></td></tr><tr><td>Pre-op</td><td>46.1±1.0 ] ns</td><td>48.0±1.2 ] ns</td><td>ns</td></tr><tr><td>Post-op</td><td>44.0±1.5 ] ns</td><td>47.7±2.4 ] ns</td><td>ns</td></tr><tr><td>Lipids (% energy intake)</td><td></td><td></td><td></td></tr><tr><td>Pre-op</td><td>34.0±0.9 ] *</td><td>31.8±1.3 ] ns</td><td>*</td></tr><tr><td>Post-op</td><td>37.4±3.1 ] *</td><td>32.6±1.9 ] ns</td><td>*</td></tr><tr><td>Proteins (% energy intake)</td><td></td><td></td><td></td></tr><tr><td>Pre-op</td><td>20.0±0.6 ] ns</td><td>20.1±0.7 ] ns</td><td>ns</td></tr><tr><td>Post-op</td><td>18.8±0.6 ] ns</td><td>19.6±1.0 ] ns</td><td>ns</td></tr></tbody></table>

Means ± SD; *, p<0.05; **, p<0.01; ***, p<0.001; ns, not significant.
Pre-op) vs post-op, paired Student; VSG vs RYGB, Student. Op, operated.

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## 3.2. *Impacts of VSG and RYGB on the orosensory perception of lipid and sweet stimuli.*

LA perception thresholds were characterized by a great inter-individual variability at the origin of a large distribution covering 4 orders of magnitude (Fig. 2-A). In the VSG group, the mean value of LA thresholds did not differ before (pre-op) and after surgery (post-op). By contrast, a significant decrease of the mean LA threshold was observed after RYGB suggesting that this surgery procedure might improve the orosensory sensitivity to LA stimuli (Fig. 2-A). For the sweet taste, the VSG procedure did not affect the mean perception threshold which was found to be 0.55% and 0.57% sucrose before and after surgery, respectively. A similar sucrose threshold distribution was also found in the RYGB group, despite a downward trend of mean perception values after surgery (0.65% sucrose in patients before RYGB vs 0.52% after RYGB, p=0.06 – Fig. 2-B). No correlation between age and fat or sweet taste perception was found in these patients (age vs LA perception thresholds, r=0.003, p=0.77; age vs sucrose perception thresholds, r=0.108, p=0.77).

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<figure><img src="image_4.png" /><figcaption>Fig. 2</figcaption></figure>

**Figure 2.** A- Linoleic acid (LA) and B- sucrose orosensory perception thresholds before and 6 months after vertical sleeve gastrectomy (VSG) or Roux-en-Y gastric bypass (RYGB) using the 3-alternative force-choice tests. Ascending concentrations of LA (from 0.00028% to 5% LA with 0.25 log units space, wt/wt) and sucrose (from 0.2 to 1.6% sucrose with increments of 0.2g, wt/wt) were tested. Geometric means. Comparisons of perception thresholds before vs after surgery were performed using a paired Wilcoxon-Pratt test. *, p<0.05. Pre-op, pre-operated; post-op, post-operated.

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## 3.3. *Changes in subjective food sensations after VSG or RYGB.*

An improvement of taste sensations (i.e. sensitivity and intensity), was reported by the most of the patients whatever the procedure used (Table 3). Subjective changes in the orosensory perception (e.i. increased sensitivity) mainly concerned the sweetness, followed by the fattiness, and in the lesser extent the saltiness (Table 3). Although the changes in the bitterness perception was more rarely reported, its frequency was found to be slightly higher after RYGB than VSG (25% of patients vs 3%, p=0.056 – Table 3).

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Whether a comparable change of fatty, salty and bitter taste intensity was reported by the two groups of patients, a more marked upward trend was observed for the sweet taste after RYGB (p=0.07 – Table 3). Post-operative impacts on olfactory performance were reported by less than half of patients (Table 3).

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<table><caption>Table 3. Reported gustatory and olfactory changes (TOC questionnaire) 6 months after surgery</caption><thead><tr><th></th><th>VSG (n=32)</th><th>RYGB (n=12)</th><th>p</th></tr></thead><tbody><tr><td><strong>Taste changes</strong></td><td></td><td></td><td></td></tr><tr><td>Increased taste (% of patients)</td><td>56</td><td>75</td><td>ns</td></tr><tr><td>Intensity of change (1-10)</td><td>6.4 ± 2.0</td><td>6.0 ± 1.1</td><td>ns</td></tr><tr><td><strong>Increased sweet taste</strong> (% of patients)</td><td>78</td><td>75</td><td>ns</td></tr><tr><td>Intensity of change (1-10)</td><td>4.9 ± 3.1</td><td>6.9 ± 1.6</td><td>0.071</td></tr><tr><td><strong>Increased fat taste</strong> (% of patients)</td><td>69</td><td>67</td><td>ns</td></tr><tr><td>Intensity of change (1-10)</td><td>6.4 ± 2.7</td><td>7.8 ± 1.8</td><td>ns</td></tr><tr><td><strong>Increased salt taste</strong> (% of patients)</td><td>50</td><td>58</td><td>ns</td></tr><tr><td>Intensity of change (1-10)</td><td>5.6 ± 2.4</td><td>5.0 ± 2.4</td><td>ns</td></tr><tr><td><strong>Increased bitter taste</strong> (% of patients)</td><td>3</td><td>25</td><td>0.056</td></tr><tr><td>Intensity of change (1-10)</td><td>6.0 ± 1.6</td><td>6.3 ± 1.2</td><td>ns</td></tr><tr><td><strong>Olfactory change</strong> (% of patients)</td><td>50</td><td>33</td><td>ns</td></tr><tr><td>Increased olfaction (% of patients)</td><td>41</td><td>25</td><td>ns</td></tr><tr><td>Intensity of change (1-10)</td><td>5.7 ± 1.8</td><td>4.3 ± 1.2</td><td>ns</td></tr></tbody></table>

Means ± SD; ns, not significant; p = X² test of Fisher exact test.

### 3.4. Impacts of bariatric surgery on the fat and sweet taste is not the same in all operated patients.

To further explore the putative effects of bariatric surgery on the fatty and sweet taste, LA and sucrose thresholds before and after surgery were compared in each of patients. This investigation has allowed to distinguish two subgroups whatever the surgery procedure used: patients displaying an improved sensitivity after surgery (i.e. lower thresholds) for fatty taste (Fig. 3-A) or sweet taste (Fig. 3-B) and non-improved patients. Improvement of the orosensory perception of both LA and sucrose was found only in a limited number of subjects (i.e. VSG+RYBG, n=10). This incidence seems to be greater after RYGB (5/12 patients, 41.6%) than after VSG (5/32 patients, 15.6% - Fig. 3-C). Complementary investigations are needed to validate this assumption. It is noteworthy that the double improved (i.e. LA and sucrose) patients (n=10, Fig. 3-C) displayed a similar weight loss and pre- and post-operative BMI than not improved patients (n=12, Fig. 3-C). These patients reported similar energy intake and composition (four-day food recall - Fig. 3-D).

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<figure><img src="image_5.png" /><figcaption>Fig. 3</figcaption></figure>

**Figure 3.** A- Comparison of linoleic acid (LA) orosensory perception thresholds before and 6 months after vertical sleeve gastrectomy (VSG) or Roux-en-Y gastric bypass (RYGB) in improved and not-improved patients. Ascending concentrations of LA (from 0.00028% to 5% LA with 0.25 log units space, wt/wt) were checked. B- Comparison of linoleic acid (LA) orosensory perception thresholds before and 6 months after vertical sleeve gastrectomy (VSG) or Roux-en-Y gastric bypass (RYGB) in improved and not-improved patients. Ascending concentrations of sucrose (from 0.2 to 1.6% sucrose with increments of 0.2g, wt/wt were checked. Geometric means. using a paired Wilcoxon-Pratt test. \*, p<0.05. Pre-op, pre-operated; post-op, post-operated. C- Repartition of improved and not-improved patients. D- Comparison of weight loss, body mass index (BMI) and reported energy intake and composition using the four-day food recall in LA/sucrose-improved and not-improved patients. \*,\* p < 0.01; \*,\*\* p < 0.001; ns, non-significant.

### 3.5. Relationships between appetite-regulating peptides and sweet and fatty taste perception after VSG or RYGB.

To explore whether appetite regulating hormones might play a role in the improvement of the orosensory perception of fat and sugar, plasma insulin, GLP-1, PYY and ghrelin levels in response to a test meal were assayed before and after surgery. Meal-induced secretion of GLP1 and PYY increased after both surgeries (Fig. 4-A), this up-regulation being significantly higher in the RYGB group. The ghrelin secretion was only affected by the VSG surgery (Fig. 4-B). In contrast to VSG, RYGB patients exhibited an improved insulin secretion after the test meal (Fig. 4). The possible links between these changes in hormonal secretions and LA or sucrose perception thresholds were analyzed in the whole cohort by using Spearman correlations, but no significant association was found (see, Table 1-S in Supplemental data).

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Comparison of subjects with and without improvement of LA and sucrose perception thresholds did not show any significant difference in the hormonal responses to the test meal, excepted insulin that was more increased in patients displaying LA threshold improvement (Supplemental data, Table 2-S).

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<figure><img src="image_6.png" /><figcaption>Fig. 4</figcaption></figure>

**Figure 4.** Plasma levels of appetite regulating peptides following a test meal before (pre-op) and 6 months after surgery (post-op). **A**- Kinetic of endocrine response. **B**- Comparison of plasma endocrine levels 30 min (t30) after the test meal in patients having undergone a vertical sleeve gastrectomy (VSG) or a Roux-en-Y gastric by-pass (RYGB). Glucagon like peptide (GLP-1); peptide YY (PYY). \*, *p* < 0.05; \*,\* *p* < 0.01; \*,\*,\* *p* < 0.001.

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Global analysis of these post-ingestive endocrine changes using the PCA method did not allow to distinguish the patients who undergone a VSG from those RYGB-operated Fig. 5-A), suggesting that the improvement of fatty taste acuity found in RYGB patients is independent of this parameter. Therefore, both surgery groups (i.e. VSG+RYGB) were combined for further analysis. In spite of the strong difference of LA perception thresholds between patients displaying a fatty taste improvement after surgery and those not improved (Fig. 3-A), the PCA did not allow to discriminate the two subgroups of patients (Fig. 5-B). A similar result was also found with sucrose alone (Fig. 5-C) or in combination with LA (Fig. 5-D).

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<figure><img src="image_7.png" /><figcaption>Fig. 5</figcaption></figure>

**Figure 5.** Principal component analysis (PCA) of gut hormones (i.e. insulin, GLP-1, PYY and Ghrelin) response to a test meal 6 months after surgery. Confidence ellipse analysis. **A-** Comparison of VSG and RYGB patients. **B-** Comparison of patients (VSG+RYGB) with and without improvement (improved vs not-improved) of the LA perception threshold. **C-** Comparison of patients (VSG+RYGB) with and without improvement (improved vs not-improved) of the sucrose perception threshold. **D-** Comparison of patients (VSG+RYGB) with and without improvement (improved vs not-improved) of the LA+ sucrose perception threshold.

## 4. Discussion

Whether the bariatric surgery may affect the fat and sweet taste sensitivity and thus contributes to the healthier food changes usually reported by the most of operated patients remains elusive. The present study was undertaken to explore further this issue. Data showing herein provides several new findings.

Firstly, RYGB leads to a significant decrease of LA perception thresholds (i.e. better fatty taste sensitivity) in contrast to VSG. Despite this observation needs to be further confirmed with a larger number of patients, this original data strongly suggests that the change of the oral fat perception after obesity surgery might be dependent on the procedure used. It is noteworthy that the magnitude of the weight loss does not explain the difference between the two surgeries, VSG and RYBG patients displaying a similar BMI and fat mass before and after surgery in our study. Although the impact of BMI as variable in the oral lipid sensitivity is a matter of debate in humans [24], this conclusion is consistent with the systematic review of the literature [29]. A recent study using taste strip tests to evaluate the lipid detection thresholds in patients has reported an improvement of sensitivity to oleic acid stimuli 6 months after bariatric surgery including VSG [35]. This inconsistency with the present data might be due to olfactory inputs, patients not wearing nose clips in this study. Contrary to lipids, sucrose perception thresholds were similar in VSG and RYGB groups and remained unchanged after surgery. This result corroborates recent studies using similar psychophysical tests [15,16]. In contrast, an increased sweet taste sensitivity after surgery was mainly reported in strip test studies [19-21] suggesting that the orosensory perception threshold assessment of lipid and sweet stimuli is highly dependent on the sensory methods used (3-AFC vs strip test). Collectively, our data show that the RYGB procedure only affects the orosensory perception of lipids suggesting that fat and sweet taste sensitivity might be differently regulated.

Secondly using a direct measurement of the taste sensitivity, our data have highlighted that the impact of bariatric surgery on the fat and sweet taste is not homogeneous in all the patients, some displaying an improvement of sensitivity for LA and/or sucrose while in others fat and sweet taste sensitivity remained unchanged or even were degraded. This disparity is reminiscent to what was already found for the fat taste in subjects with obesity [33]. The

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similar daily caloric intake and energetic nutrient distribution found in double-improved (i.e. LA and sucrose) and unimproved patients suggests a disconnection between the orosensory perception performance and eating behavior. Such segregation between subjective food sensations and measured oral fat and sweet perception was already found by others (for a review, [12]). Moreover, the present changes in food selection were evaluated using a self-reporting method (i.e. 4-day food recall questionnaire) known to produce biased responses. Indeed, patients with obesity tend to underreport their consumption of energetic-dense foods [36]. Whether the improvement of the fatty and sweet taste found in some patients drives a healthier ingestive behavior remains thus to be further clarified using a direct method to measure accurately the changes in food selection (e.g. *ad libitum* buffet paradigm – [37]).

Thirdly, the changes in gut hormones observed in our study are in accordance to previous data [30,38]. A large body of evidence supports that the beneficial metabolic effects and the successful weight loss of RYGB and VSG are elicited by changes of appetite-regulating peptides secretion in response to a meal, especially insulin, GLP-1, PYY and ghrelin In contrast to the well-documented remission of type-2 diabetes [39] and the promotion of satiety [40], effects of these endocrine changes on the gustatory function remains elusive [41]. Indeed, they are mainly supported by indirect observations frequently derived from animal models: presence of receptors from appetite-regulating hormones in taste bud cells, endocrine modulation of taste perception, self-reported improvement of taste sensations (sensitivity and intensity) after surgery. Using a multivariate statistical method (PCA), we have found that this new hormonal environment is insufficient to discriminate patients with an improved orosensory perception of LA and/or sucrose after surgery from non-improved patients. This finding strongly suggests that the gustatory regulation by hormones from the digestive tract, if it exists in human, has a very limited impact on this parameter. The fact that taste bud cells express appetite-regulatory peptides and their cognate receptors suggests rather a local (i.e. at the level of the gustatory papillae) than a peripheral (i.e. at the level of the digestive tract) endocrine control of the taste function.

Finally, according to previous studies (for a review see, [12]), we found that subjective changes in food sensations reported by the most of patients after surgery (i.e. increased sensitivity and intensity to fat and sweet stimuli) are not corroborated by the direct measure of taste perception using a validated method, excepted for fat after RYGB. This lack of causal link suggests that self-reported changes might result from other mechanisms as, for example, a modification of rewarding value of foods [24].

The main weakness of our study is the low number of patients included in the RYGB group (n=12) as compared to VSG group (n=32). This imbalance reflects the current tendency to favor the VSG procedure by reason of reduced post-surgery complications [42]. Despite this limitation, it is noteworthy that our study reproduces the lack of change in the sucrose perception thresholds found with a greater number of RYGB patients (n=23) [16]. Moreover, the fact that investigations were performed only in women who were their own controls has likely reduced the possible biases due to gender and inter-individual variability [25]. Finally, to optimize the reproducibility of psychophysical data, the 3-AFC tests were performed in the morning by the same experimenter in fasted patients having eaten the same standardized meal the night before.

In conclusion, despite that the most of patients self-reports a better orosensory perception of fattiness and sweetness whatever surgery procedure used, improvement of fat and sweet taste perception is only found in few ones, with the exception of RYGB patients predominantly more sensitive to the taste of fat after surgery. The lack of evident implication of appetite regulatory hormones in these surgery-mediated orosensory changes emphasizes the complexity of mechanistic events linking obesity, and conversely bariatric surgery, to perceived food sensations. Whether the improvement of fat after RYGB procedure provides physiological advantages to these patients contributing, for example, to the long-term success of surgery remains to be explored. Understanding of underlying mechanisms might be useful to segregate improved from non-improved patients in the future in order to offer them an early personalized therapy promoting a long-term weight loss.
**ACKNOWLEDGEMENTS:** The authors thank Véronique Le Stanguennec and Patricia Clair from the Service d'Explorations Fonctionnelles, Hôpital Louis Mourier (APHP), Salma Fourati and Clément Janot from the Service de Biochimie Endocrinienne et Oncologique, Groupe Hospitalier Pitié-Salpêtrière (APHP) for their technical assistance, Jérôme Labbé from the UMR 1231 Lipides, Nutrition, Cancer from INSERM and UBFC for its administrative support.

**Funding:** This study was supported by financial support from Avril, Tereos and Benjamin

**AUTHORS' CONTRIBUTIONS:** The authors' responsibilities were as follows: SL, PB, AB, CLM, XC, PD, CLB: designed the research; AB, SL, LR, MC, OS, NC: conducted the research; SL, PB, AB: analyzed data; SL, PB, AB: wrote the manuscript; SL and PB: had primary responsibility for the final content of the manuscript. All authors: read and approved the final manuscript.

**Abbreviations:** 3-AFC: three alternative-force choice; BMI, body mass index; GLP-1, glucagon-like peptide-1; LA, linoleic acid; PCA, principal component analysis; PYY, peptide YY; RYGB, Roux-en-Y gastric by-pass; TOC, taste and olfactory changes questionnaire; VSG, vertical sleeve gastrectomy.

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