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International audience; Introduction: N3 polyunsaturated fatty acids (n-3 PUFAs) exert anti-inflammatory effects for the hypothalamus, but their extra-hypothalamic outcome lack documentation. We evaluated the central consequences of the substitution of saturated fatty acids with n-3 or n-6 PUFA in obesogenic diets.Methods: Twenty-one miniature pigs were fed ad libitum obesogenic diets enriched in fat provided either as lard, fish oil (source for n-3 PUFAs), or sunflower oil (source for n-6 PUFAs) for ten weeks. The blood-brain barrier (BBB) permeability was quantified by CT perfusion. Central autonomic network was evaluated using heart rate variability, and PET 18FDG was performed to assess brain metabolism.Results: BBB permeability was higher in lard group, but heart rate variability changed only in fish oil group. Brain connectivity analysis and voxel-based comparisons show regional differences between groups except for the cingulate cortex in fish oil vs. sunflower oil groups.Discussion: : The minute changes in brain metabolism in obese pigs feed with fish oil compared with saturated fatty acids were sufficient to induce detrimental changes in heart rate variability. On the contrary, the BBB's decreased permeability in n-3 and n-6 PUFAs groups was protective against an obesity-driven damaged BBB.

International audience; BACKGROUND: Uterine transplant (UT) represents an opportunity to treat absolute uterine infertility. However, the use of uterine veins for venous return, in addition to ovarian veins, significantly increases the risk of ureteral wounds in the living donor and UT time for the recipient. Our aim was to demonstrate that dual ovarian venous return is sufficient for graft viability and survival. METHODS: Uterine orthotopic auto-transplant was performed under general anaesthesia in six Yucatan minipig sows. The uterus graft was implanted with termino-lateral anastomoses between the ovarian and external iliac veins, and between the uterine and external iliac arteries, respectively. RESULTS: The macroscopic physical aspect of the graft was adequate in 83 % of the sows (5/6) 30 min after reperfusion with a surgical time of 439±54 min (mean anastomosis time: 153±49 min). Two sows died the day after surgery. In the four remaining sows, two uteri were necrotic and two were adequately vascularized on Day 7. CONCLUSIONS: the learning curve was relatively fast, the sole use of bilateral ovarian venous return is possible and might reduce post-surgery morbidity in human living donors as well as UT time for the recipient.

Context Hypoglycemia is a major barrier to optimal glycemic control in insulin-treated diabetes. Recent guidelines from the American Diabetes Association have subcategorized “non-severe” hypoglycemia into level 1 ( Objective To determine the effects of 2 levels of hypoglycemia, 2.6 mmol/L (“marked”) and 3.6 mmol/L (“mild”), on gastric emptying in health. Design, Setting, and Subjects Fourteen healthy male participants (mean age: 32.9 ± 8.3 years; body mass index: 24.5 ± 3.4 kg/m2) from the general community underwent measurement of gastric emptying of a radiolabeled solid meal (100 g beef) by scintigraphy over 120 minutes on 3 separate occasions, while blood glucose was maintained at either ~2.6 mmol/L, ~3.6 mmol/L, or ~6 mmol/L in random order from 15 minutes before until 60 minutes after meal ingestion using glucose-insulin clamp. Blood glucose was then maintained at 6 mmol/L from 60 to 120 minutes on all days. Results Gastric emptying was accelerated during both mild (P = 0.011) and marked (P = 0.001) hypoglycemia when compared to euglycemia, and was more rapid during marked compared with mild hypoglycemia (P = 0.008). Hypoglycemia-induced gastric emptying acceleration during mild (r = 0.57, P = 0.030) and marked (r = 0.76, P = 0.0014) hypoglycemia was related to gastric emptying during euglycemia. Conclusion In health, acceleration of gastric emptying by insulin-induced hypoglycemia is dependent on the degree of hypoglycemia and baseline rate of emptying.

International audience; Background: Here we present an open-source solution, comprising several 3D-printable mechanical pieces and software tools, for frameless stereotaxic targeting in young and adult pigs of varying weights.New metbod: Localization was achieved using an IR camera and CT imaging. The positions of the tools were followed, after registration of the pig stereotaxic space, with a CT scan and open-source brain atlas. The system was used to target the lateral ventricle and the subthalamic nucleus (STN) in one piglet and two adult Yucatan miniature pigs, which were either normal weight or obese.Results and conclusions: Positive targeting was confirmed in the first trial for all subjects, either by radiopaque CT enhancement of the ventricle or actual recording of the STN electrophysiological signature. We conclude that open-source freely available models, easily built with low-end 3D printers, and their associated software can be effectively used for brain surgery in pigs, at a minimal cost, irrespective of the weight of the animal.

International audience; Signals arising from the upper part of the gut are essential for the regulation of food intake, particularly satiation. This information is supplied to the brain partly by vagal nervous afferents. The porcine model, because of its sizeable gyrencephalic brain, omnivorous regimen, and comparative anatomy of the proximal part of the gut to that of humans, has provided several important insights relating to the relevance of vagally mediated gut-brain relationships to the regulation of food intake. Furthermore, its large size combined with the capacity to become obese while overeating a western diet makes it a pivotal addition to existing murine models, especially for translational studies relating to obesity. How gastric, proximal intestinal, and portal information relating to meal arrival and transit are encoded by vagal afferents and their further processing by primary and secondary brain projections are reviewed. Their peripheral and central plasticities in the context of obesity are emphasized. We also present recent insights derived from chronic stimulation of the abdominal vagi with specific reference to the modulation of mesolimbic structures and their role in the restoration of insulin sensitivity in the obese miniature pig model.

usc The glucose portal sensor informs the brain of changes in glucose inflow through vagal afferents that require an activated glucagon-like peptide 1 receptor (GLP-1r). The GLP-1 system is known to be impaired in insulin-resistant conditions, and we sought to understand the consequences of GLP-1 resistance on glucose portal signaling. GLP-1–dependent portal glucose signaling was identified, in vivo, using a novel 68Ga-labeled GLP-1r positron-emitting probe that supplied a quantitative in situ tridimensional representation of the portal sensor with specific reference to the receptor density expressed in binding potential units. It also served as a map for single-neuron electrophysiology driven by an image-based abdominal navigation. We determined that in insulin-resistant animals, portal vagal afferents failed to inhibit their spiking activity during glucose infusion, a GLP-1r–dependent function. This reflected a reduction in portal GLP-1r binding potential, particularly between the splenic vein and the entrance of the liver. We propose that insulin resistance, through a reduction in GLP-1r density, leads to functional portal desensitization with a consequent suppression of vagal sensitivity to portal glucose. Refereed/Peer-reviewed

Palatable sweet/fatty foods overconsumption is a major risk factor for obesity and eating disorders, also having an impact on neuro-behavioural hedonic and cognitive components comparable to what is described for substance abuse. We hypothesized that Yucatan minipigs would show hedonic, cognitive, and affective neuro-behavioral shifts when subjected to western diet (WD) exposure without weight gain, after the onset of obesity, and finally after weight loss induced by caloric restriction with (RYGB) or without (Sham) gastric bypass. Eating behavior, cognitive and affective abilities were assessed with a spatial discrimination task (holeboard test) and two-choice feed tests. Brain responses to oral sucrose were mapped using 18F-FDG positron emission tomography. WD exposure impaired working memory and led to an “addiction-type” neuronal pattern involving hippocampal and cortical brain areas. Obesity induced anxiety-like behavior, loss of motivation, and snacking-type eating behavior. Weight loss interventions normalized the motivational and affective states but not eating behavior patterns. Brain glucose metabolism increased in gustatory (insula) and executive control (aPFC) areas after weight loss, but RYGB showed higher responses in inhibition-related areas (dorsal striatum). These results showed that diet quality, weight loss, and the type of weight loss intervention differently impacted brain responses to sucrose in the Yucatan minipig model.

Introduction The insulinotropic capacity of exogenous glucagon like peptide-1 (GLP-1) is reduced in type 2 diabetes and the insulin-resistant obese. We have tested the hypothesis that this response is the consequence of a reduced pancreatic GLP-1 receptor (GLP-1r) density in insulin-resistant obese animals. Research design and methods GLP-1r density was measured in lean and insulin-resistant adult miniature pigs after the administration of a 68 Ga-labeled GLP-1r agonist. The effect of hyperinsulinemia on GLP-1r was assessed using sequential positron emission tomography (PET), both in the fasted state and during a clamp. The impact of tissue perfusion, which could account for changes in GLP-1r agonist uptake, was also investigated using 68 Ga-DOTA imaging. ResultsGLP-1r binding potential in the obese pancreas was reduced by 75% compared with lean animals. Similar reductions were evident for fat tissue, but not for the duodenum. In the lean group, induced hyperinsulinemia reduced pancreatic GLP-1r density to a level comparable with that of the obese group. The reduction in blood to tissue transfer of the GLP-1r ligand paralleled that of tissue perfusion estimated using 68 Ga-DOTA.ConclusionsThese observations establish that a reduction in abdominal tissue perfusion and a lower GLP-1r density account for the diminished insulinotropic effect of GLP-1 agonists in type 2 diabetes.

International audience; Palatable sweet/fatty foods overconsumption is a major risk factor for obesity and eating disorders, also having an impact on neuro-behavioural hedonic and cognitive components comparable to what is described for substance abuse. We hypothesized that Yucatan minipigs would show hedonic, cognitive, and affective neuro-behavioral shifts when subjected to western diet (WD) exposure without weight gain, after the onset of obesity, and finally after weight loss induced by caloric restriction with (RYGB) or without (Sham) gastric bypass. Eating behavior, cognitive and affective abilities were assessed with a spatial discrimination task (holeboard test) and two-choice feed tests. Brain responses to oral sucrose were mapped using 18F-FDG positron emission tomography. WD exposure impaired working memory and led to an “addiction-type” neuronal pattern involving hippocampal and cortical brain areas. Obesity induced anxiety-like behavior, loss of motivation, and snacking-type eating behavior. Weight loss interventions normalized the motivational and affective states but not eating behavior patterns. Brain glucose metabolism increased in gustatory (insula) and executive control (aPFC) areas after weight loss, but RYGB showed higher responses in inhibition-related areas (dorsal striatum). These results showed that diet quality, weight loss, and the type of weight loss intervention differently impacted brain responses to sucrose in the Yucatan minipig model.

International audience; Objective: This study evaluated gastric emptying (GE) and small intestinal (SI) transit in people with morbid obesity and their relationships to glycaemia, incretin hormones, and glucose absorption Methods: GE and caecal arrival time (CAT) of a mixed meal were assessed in 22 morbidly obese (50.2 +/- 2.5 years; 13 F:9 M; BMI: 48.6 +/- 1.8 kg/m(2)) and 10 lean (38.6 +/- 8.4 years; 5 F:5 M; BMI: 23.9 +/- 0.7 kg/m(2)) subjects, using scintigraphy. Blood glucose, plasma 3-O-methylglucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured. Insulin sensitivity and resistance were also quantified Results: When compared with lean subjects, GE (t50: 60.7 +/- 6.5 vs. 41.1 +/- 7.3 min; P = 0.04) and CAT (221.5 +/- 9.8 vs. 148.0 +/- 7.1 min; P = 0.001) of solids were prolonged in morbid obesity. Postprandial rises in GIP (P = 0.001), insulin (P = 0.02), glucose (P = 0.03) and 3-O-methylglucose (P = 0.001) were less. Whereas GLP-1 increased at 45 mins postprandially in lean subjects, there was no increase in the obese (P = 0.04). Both fasting (P = 0.045) and postprandial (P = 0.012) plasma glucagon concentrations were higher in the obese Conclusions: GE and SI transit are slower in the morbidly obese, and associated with reductions in postprandial glucose absorption, and glycaemic excursions, as well as plasma GIP and GLP-1

International audience; Aims: To evaluate the effects of 8 weeks’ administration of exenatide (EXE) once weekly on gastric emptying of solids and liquids (using the “gold standard” technique, scintigraphy), glucose absorption and postprandial glycaemia in healthy people.Material and methods: A total of 32 healthy participants were randomized to receive either EXE once weekly (2 mg/wk subcutaneously; six men, 10 women, mean age 59.9 ± 0.9 years, mean body mass index [BMI] 29.6 ± 0.6 kg/m2) or matching placebo (PBO; six men, 10 women, mean age 60.6 ± 1.2 years, mean BMI 29.5 ± 1.0 kg/m2) for 8 weeks. Gastric emptying, nausea (visual analogue scale), and plasma glucose, insulin, C-peptide and glucagon were measured for 120 min after a solid/liquid meal, comprising 100 g ground beef (radiolabelled with 20 MBq 99mTc-sulphur colloid) and 150 mL 10% glucose (radiolabelled with 7 MBq 67Ga-EDTA), and containing 5 g 3-O-methyl-glucose (3-OMG) as a marker of glucose absorption, at baseline and after 8 weeks’ treatment.Results: The study treatments were well tolerated. Scores for nausea were consistently low, with no difference between the EXE once weekly and PBO groups. EXE once weekly slowed gastric emptying of solids (area under the curve [AUC]0–120min: P

Lower binding potential of GLP-1 receptor in the pancreas as a consequence of diet-induced obesity. 32. Annual Congress of the European-Association-of-Nuclear-Medicine (EANM)

International audience; Background and aims: The rate of gastric emptying (GE) of carbohydrate is a major determinant of postprandial glycaemia. ‘Marked’ hypoglycaemia (~2.6mmol/L) accelerates GE substantially in both health and Type 1 diabetes and is likely to represent an important counter-regulatory mechanism by increasing the rate of carbohydrate absorption. There is no information about the effect of ‘mild’ hypoglycaemia (between 3.0-3.9mmol/L) on GE, which is more common in clinical practice. We have evaluated the effects of two levels of insulin-induced, hypoglycaemia i.e. ‘mild’ (blood glucose ~3.6mmol/L) and ‘marked’ (blood glucose ~2.6mmol/L) when compared to ‘euglycaemia’ (6mmol/L) on GE in health. Materials and methods: Nine healthy males (mean age: 33.9 ± 1.0 yrs; BMI 23.4 ± 1.3 kg/m2; HbA1c: 5.3 ± 0.6%) underwent concurrent measurements of GE of a solid meal (100g minced beef radio-labelled with 99mTc) by scintigraphy and arterialised venous blood glucose by glucose-oxidase analyser, on 3 separate occasions during ‘mild’ and ‘marked’ hypoglycaemia, and ‘euglycaemia’, in random order. Hypoglycaemia (~2.6mmol/L or ~3.6mmol/L) was established using a glucose-insulin clamp 15min before (t=-15min), and maintained for a further 60min (t=60 min) after, meal consumption. At t=60min, blood glucose was returned to 6mmol/L and maintained from t=60-120 min. On the ‘euglycaemia’ study day, blood glucose was clamped at ~6mmol/L and maintained at that level for the duration of the study. GE was measured for 120min after meal ingestion and expressed as % retention over time. Data are shown as mean ± SEM (Figure). A maximumlikelihood mixed effects model was used to estimate the difference in area under the curve (AUC) for gastric retention between glycaemic treatments with Bonferroni-adjusted pairwise comparisons of the estimated marginal means. A P-value Results: There was an overall effect of glycaemia on gastric retention such that gastric emptying was accelerated during both ‘mild’ and ‘marked’ hypoglycaemia compared to euglycaemia as reflected by the AUC0-120min (PConclusion: The effect of hypoglycaemia to accelerate GE is dependent on the degree of hypoglycaemia in health. While both ‘mild’ and ‘marked’ hypoglycaemia accelerate gastric emptying substantially, the effect of ‘marked’ hypoglycaemia is greater.

International audience; Background and aims: A whey protein/guar preload (Omniblend Innovation) has been developed recently to reduce postprandial glycaemia. The preload comprises 5g guar, 20g (whey) protein and 3g lactose (total 90kcal) in a sachet, which is added to a ‘shake and take’ cup containing 150ml water. Our previous trial suggested that this supplement slowed gastric emptying (GE), but the latter was assessed using a stable isotope breath test technique which limits the capacity to discriminate between slowing of GE and a delay in intestinal absorption. Our aim was to determine the effects of this guar/whey protein preload on GE (using the ‘gold standard’ technique, scintigraphy), and the glycaemic/ insulinaemic responses to an oral glucose load in healthy older people. Materials and methods: Ten healthy older participants (6F, 4M; age: 74.0 ± 1.6 yr; BMI: 26.0 ± 0.7 kg/m2) with normal glucose tolerance underwent concurrent measurements of GE, plasma glucose and insulin for 180 min on two occasions. Participants were studied after an overnight fast, were seated with their back against a gamma camera and a cannula inserted into an antecubital vein for blood sampling. In random order, each received a test drink comprising 50g glucose made up to 300ml with water containing 20MBq 99mTc-calcium-phytate with or without the guar/whey protein preload (90kcal) made up to 150ml with water, ingested 15 min before the test drink. Blood samples were taken immediately before the preload, before the glucose test drink and at 15-30 min intervals thereafter until t=180 min. The early insulin secretory response was estimated by the ratio of the change in insulin (ΔI0-30) to that of glucose at 30 min (ΔG0-30) represented as ΔI0-30/ΔG0-30. Data are mean values ± SEM. Results: The guar/whey protein preload reduced both the iAUC0-120 (PConclusion: In healthy older people, the glucose-lowering effect of the whey protein/guar preload appears unrelated to changes in GE and may reflect increased insulin secretion and/or slowing of small intestinal absorption.

International audience; Background and aims: Glucagon-like peptide-1 agonists (GLP-1RAs) induce weight loss in obese patients and, particularly with ‘short-acting’ GLP-1RAs, slow gastric emptying (GE). In healthy subjects, energy intake after a nutrient ‘preload’ is more strongly related to the content of the distal, than the total, stomach. The effect of GLP-1RAs on intragastric meal distribution has not been reported.We evaluated the acute effects of lixisenatide (LIXI) on intragastric distribution of a glucose drink and subsequent energy intake in health and type 2 diabetes (T2DM). Materials and methods: 15 healthy subjects (9M, 6F; age: 67.2 ± 2.3 yr; BMI: 25.4 ± 0.8 kg/m2) and 15 T2DMpatients managed by diet ormetformin (9M, 6F; age: 61.9 ± 2.3 yr; BMI: 30.3 ± 0.7 kg/m2; duration of known diabetes: 5.3 ± 1.2 yr; HbA1c: 6.9 ± 0.2%were studied. All subjects received LIXI (10mcg sc) or placebo (PLAC) on 2 separate days in a randomised, double-blind, crossover fashion 30 min before a 75g glucose drink labelled with 20MBq 99mTc-Calcium Phytate. A lower than usual dose of LIXI was used to maximise tolerability. GE was measured by scintigraphy for 180 min. A region-of-interest was drawn around the total stomach, which was divided into proximal and distal stomach regions. At 180 min each participant was offered a buffet meal and allowed to eat for 30 min to assess subsequent energy intake. Nausea was measured, using a visual analogue questionnaire, prior to receiving study drug, before the drink and at regular intervals during the study. Data are mean ± SEM and PResults: The studies were well tolerated; scores for nausea were uniformly lowwith no difference between PLAC and LIXI in either group. LIXI slowed GE (% total stomach retention at 180 min - health: PLAC 16.0 ± 11.1 vs LIXI 59.5 ± 24.6 ; T2DM: PLAC 14.5 ± 7.5 vs LIXI 54.4 ± 27.5) and increased retention in both the proximal stomach (health: PLAC 6.6 ± 3.5 vs LIXI 40.9 ± 24.6 ; T2DM: PLAC 6.3 ± 4.1 vs LIXI 34.8 ± 24.5) and distal stomach (health: PLAC 9.4 ± 9.1 vs LIXI 18.6 ± 11.1 ; T2DM: PLAC 8.2 ± 4.2 vs LIXI 19.6 ± 10.4); P

International audience; Background and aims: ‘Short-acting’ glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) lower postprandial glucose predominantly via their profound effect to slow gastric emptying (GE). It is generally assumed that ‘long-acting’ GLP-1RAs have little, if any, effect on GE with longer-term administration, reflecting ‘tachyphylaxis’ to slowing of GE as a result of sustained receptor exposure. However, information relating to the effect of ‘long-acting’ GLP-1RAs on GE is limited and previous studies have been compromised by the use of suboptimal methodology to quantify GE. We evaluated the effects of 8 weeks’ administration of exenatide once-weekly (ExQW) on GE of solids and liquids (using the ‘gold standard’ technique, scintigraphy), postprandial glycaemia and glucose absorption in health. Materials and methods: Thirty two healthy participants completed an 8-week double-blind, placebo-controlled, parallel-group designed study. Participants were randomised to receive either ExQW (2mg sc) (6M, 10F; mean age: 59.9 ± 0.9yr; BMI: 29.6 ± 0.6 kg/m2) or matched placebo (PLAC) (6M, 10F; mean age: 60.6 ± 1.2yr; BMI: 29.5 ± 1.0 kg/m2). GE, nausea (100mm visual analogue scale) and plasma glucose, insulin, C-peptide, glucagon were measured for 120 min after a mixed solid/liquid meal, comprising 100g minced beef radiolabelled with 20MBq 99mTc-sulphur colloid and 150ml 10% glucose radiolabelled with 7MBq 67Ga-EDTA and containing 5g 3-O-methyl-glucose (3-OMG) to assess oral glucose absorption, at baseline and after 8 weeks’ administration. Data are shown as mean values ± SEM and a PResults: The studies were well-tolerated. Scores for nausea were consistently very low and there was no difference between ExQW and PLAC groups at either baseline or after treatment. ExQW slowed GE of both solids (AUC0-120: P=0.05) and liquids (AUC0-120: P=0.01) substantially (Figure) and attenuated both the postprandial rise in plasma glucose (e.g. iAUC0-30: P=0.008) and glucose absorption (e.g. 3-OMG iAUC0-30: P=0.001). There were no differences in plasma insulin, C-peptide or glucagon between the two groups. The magnitude of the reduction in plasma glucose at t=30 min from baseline to 8 weeks with ExQW was inversely related to the 50% emptying time of the glucose drink (r=-0.55, P=0.03) i.e. postprandial glucose-lowering by ExQW was dependent on the magnitude of the slowing of GE. Conclusion: In healthy subjects, 8 weeks administration of the ‘long-acting’ GLP-1RA, ExQW, slows GE of solids and liquids with consequent reductions in glucose absorption and postprandial glycaemia.

International audience; Background : In the context of morbid obesity, vagus nerve stimulation could be used to control gastric function targeting the small afferent B-fibers and C-fibers. Compared to large A-fibers, activation thresholds of these small efferent fibers are 10 to 100 times greater, inducing technical constraints and possible nerve damages. Although rectangular waveform is commonly used in nerve stimulation, recent modeling and experimental studies suggest that non-rectangular waveforms could reduced the charge injected by the stimulator.New method : The objective of the present study is to evaluate the charge injection of complex waveforms such as the ramp, quarter sine and chopped pulses in the context of vagus nerve stimulation. We performed in-vivo study on the porcine abdominal vagus nerves and evaluated charge injection at activation thresholds. A modeling study was performed to further extent the results obtained in-vivo.Comparison with existing method : Compared to the rectangular pulse, the ramp and quarter sine waveforms activated gastric fibers with the lowest charge injection: −23.2% and −30.1% respectively. The efficacy of chopped pulses is questioned through the consideration of the strength-duration curve.Conclusion : Continuous ramp and quarter sine waveforms effectively activate small diameter fibers. These pulse shapes may be considered for long-term vagus nerve stimulation. The results predicted by computational models were qualitatively consistent with experiments. This suggested the relevance of using modeling in the context of complex waveforms prior to future in-vivo tests.

International audience; PURPOSES: Whether low-calorie sweeteners (LCS), such as sucralose and acesulfame K, can alter glucose metabolism is uncertain, particularly given the inconsistent observations relating to insulin resistance in recent human trials. We hypothesized that these discrepancies are accounted for by the surrogate tools used to evaluate insulin resistance and that PET 18FDG, given its capacity to quantify insulin sensitivity in individual organs, would be more sensitive in identifying changes in glucose metabolism. Accordingly, we performed a comprehensive evaluation of the effects of LCS on whole-body and organ-specific glucose uptake and insulin sensitivity in a large animal model of morbid obesity.METHODS: Twenty mini-pigs with morbid obesity were fed an obesogenic diet enriched with LCS (sucralose 1 mg/kg/day and acesulfame K 0.5 mg/kg/day, LCS diet group), or without LCS (control group), for 3 months. Glucose uptake and insulin sensitivity were determined for the duodenum, liver, skeletal muscle, adipose tissue and brain using dynamic PET 18FDG scanning together with direct measurement of arterial input function. Body composition was also measured using CT imaging and energy metabolism quantified with indirect calorimetry.RESULTS: The LCS diet increased subcutaneous abdominal fat by ≈ 20% without causing weight gain, and reduced insulin clearance by ≈ 40%, while whole-body glucose uptake and insulin sensitivity were unchanged. In contrast, glucose uptake in the duodenum, liver and brain increased by 57, 66 and 29% relative to the control diet group (P

Background/objective Changes in brain metabolism has been investigated thoroughly during unilateral cervical chronic vagal stimulation in epileptic or depressive patients. Bilateral stimulation of the abdominal vagus (aVNS) has received less attention despite the reduction in body weight and an altered feeding behavior in obese animals that could be clinically relevant in obese individuals. Our study aims to examine the changes in brain glucose metabolism (CMRglu) induced by aVNS in obese adult miniature pigs. Dopamine (DAT) and serotonin transporters (SERT) were also quantified to further understand the molecular origins of the alterations in brain metabolism. Subjects/methods Pairs of stimulating electrodes were implanted during laparoscopy on both abdominal vagal trunks in 20 obese adult’s miniature pigs. Half of the animals were permanently stimulated while the remaining were sham stimulated. Two months after the onset of stimulation, dynamic 18FDG PET and 123I-ioflupane SPECT were performed. Food intake, resting energy expenditure and fat deposition were also assessed longitudinally. Results Food intake was halved and resting energy expenditure was increased by 60% in aVNS group compared to sham. The gain in body weight was also 38% less in aVNS group compared to sham. Brain metabolic connectivity increased between numerous structures including striatum, mid-brain, amygdala and hippocampus. On the contrary, increased CMRglu were restricted to the thalamus, the periaqueducal grey and the amygdala. DAT binding potential was decreased by about one third in the striatum while SERT was about doubled in the midbrain. Conclusions Our findings demonstrated that aVNS reduced weight gain as a consequence of diminished daily food intake and increased resting energy expenditure. These changes were associated with enhanced connectivity between several brain areas. A lower striatal DAT together with a doubled mid-brain SERT were likely causative for these changes. Electronic supplementary material The online version of this article (10.1186/s12967-019-1831-5) contains supplementary material, which is available to authorized users.

Glucagon-like peptide-1 receptor agonists induce weight loss, which has been suggested to relate to the slowing of gastric emptying (GE). In health, energy intake (EI) is more strongly related to the content of the distal, than the total, stomach. We evaluated the effects of lixisenatide on GE, intragastric distribution, and subsequent EI in 15 healthy participants and 15 patients with type 2 diabetes (T2D). Participants ingested a 75-g glucose drink on two separate occasions, 30 min after lixisenatide (10 mcg) or placebo subcutaneously, in a randomised, double-blind, crossover design. GE and intragastric distribution were measured for 180 min followed by a buffet-style meal, where EI was quantified. Relationships of EI with total, proximal, and distal stomach content were assessed. In both groups, lixisenatide slowed GE markedly, with increased retention in both the proximal (p &lt, 0.001) and distal (p &lt, 0.001) stomach and decreased EI (p &lt, 0.001). EI was not related to the content of the total or proximal stomach but inversely related to the distal stomach at 180 min in health on placebo (r = &minus, 0.58, p = 0.03) but not in T2D nor after lixisenatide in either group. In healthy and T2D participants, the reduction in EI by lixisenatide is unrelated to changes in GE/intragastric distribution, consistent with a centrally mediated effect.

Aims: Gastric emptying is a major determinant of postprandial glycaemia in both health and type 2 diabetes (T2DM); the potential impact of ethnicity on gastric emptying is unclear. We compared the rate of gastric emptying of a standardised meal and the associated glycaemic response in Han Chinese and Caucasian patients with T2DM.Methods: 14 Han Chinese and 14 Caucasian T2DM patients, managed by diet and/or metformin monotherapy, underwent concurrent measurements of gastric emptying and blood glucose for 240 min after a 99mTc-calcium phytate-labelled mashed potato meal.Results: Han Chinese patients were slightly younger (P < 0.05), and had a lower BMI (P < 0.05), than Caucasians. There were no differences in either HbA1c or fasting blood glucose between them. Gastric half-emptying time (T50) was shorter (P < 0.05) and the postprandial blood glucose increment greater (P < 0.05) in Han Chinese than Caucasian patients. Both the increment in blood glucose from baseline at 60 min and peak blood glucose were related inversely to T50 (P < 0.05 each).Conclusions: Han Chinese with relatively well-controlled T2DM have more rapid gastric emptying compared to Caucasians, which is associated with a greater postprandial glycaemic excursion. These differences may inform the choice of management, e.g. Han Chinese may particularly benefit from therapies that slow gastric emptying.

Impact of long term supplement with artificial sweeteners on insulin dependent glucose uptake. 25. European Congress on Obesity (ECO2018)

Altered brain processing after long-term artificial sweetener use. 25. European Congress on Obesity (ECO2018)

International audience; Gastric emptying of food is mainly driven by the caloric concentration, the rheological properties of the chyme, and the physical state (liquid/solid) of food once in the stomach. The present work investigated: (1) The effect of the composition and the viscosity of drinkable yogurts on gastric emptying in pigs, and (2) the behavior of yogurts during dynamic in vitro digestion. Three isocaloric liquid yogurts were manufactured: Two enriched in protein and fiber showing either a low (LV) or high (HV) viscosity, one control enriched in sugar and starch (CT). They were labelled with 99mTc-sulfur colloid and given to pigs (n = 11) to determine gastric emptying pattern by gamma scintigraphy. Then dynamic in vitro digestion of the yogurts was done using the parameters of gastric emptying determined in vivo. Gastric emptying half-times were significantly longer for LV than CT, whereas HV exhibited an intermediate behavior. In vitro gastric digestion showed a quick hydrolysis of caseins, whereas whey proteins were more resistant in the stomach particularly for LV and HV. During the intestinal phase, both whey proteins and caseins were almost fully hydrolyzed. Viscosity was shown to affect the behavior of yogurt in the small intestine.

International audience; Objective: There is a general agreement that there are changes in brain metabolism in insulin-resistant individuals during conditions of hyperinsulinemia. However, the impact on obesity is unclear, and the metabolic constants underlying these modifications are unknown. The aim of this study was to evaluate these changes in a large animal model of diet-induced obesity. Methods: Twenty adult miniature pigs were fed with either an obesogenic diet or a regular diet for 5 months. At that time, fat deposition was evaluated using computed tomography scanning, and (18)fluorodeoxyglucose positron emission tomography images were acquired dynamically both in the fasted state and during a euglycemic-hyperinsulinemic clamp. Glucose uptake rates and pixel-wise modeled brain volumes were calculated together with brain connectivity. Results: Whole-body insulin sensitivity was reduced by more than 50% in the obesity group. During insulin stimulation, whole-brain insulin-induced increased glucose uptake was unaltered in lean animals but increased markedly in the animals with obesity. The increased glucose uptake reflected an increase in the inward transfer without changes in phosphorylation or outward brain transport. Connectivity was increased in the animals with obesity Conclusions: Diet-induced obesity is associated with an increase in insulin-stimulated brain glucose uptake as a consequence of a larger inward transfer. These changes occurred together with an increased connectivity in reference to regions associated with memory recollection.

Butyrate can improve gut functions, whereas histone deacetylase inhibitors might alleviate neurocognitive alterations. Our aim was to assess whether oral butyrate could modulate brain metabolism and plasticity and if this would relate to gut function. Sixteen pigs were subjected to sodium butyrate (SB) supplementation via beverage water or water only [control (C)]. All pigs had blood sampled after 2 and 3 wk of treatment, and were subjected to a brain positron emission tomography after 3 wk. Animals were euthanized after 4 wk to sample pancreas, intestine, and brain for gut physiology and anatomy measurements, as well as hippocampal histology, Ki67, and doublecortin (DCX) immunohistochemistry. SB compared with C treatment triggered basal brain glucose metabolism changes in the nucleus accumbens and hippocampus ( P = 0.003), increased hippocampal granular cell layer volume ( P = 0.006), and neurogenesis (Ki67: P = 0.026; DCX: P = 0.029). After 2 wk of treatment, plasma levels of glucose, insulin, lactate, glucagon-like peptide 1, and peptide tyrosine tyrosine remained unchanged. After 3 wk, plasma levels of lactate were lower in SB compared with C animals ( P = 0.028), with no difference for glucose and insulin. Butyrate intake impacted very little gut anatomy and function. These results demonstrate that oral SB impacted brain functions with little effects on the gut.-Val-Laillet, D., Guérin, S., Coquery, N., Nogret, I., Formal, M., Romé, V., Le Normand, L., Meurice, P., Randuineau, G., Guilloteau, P., Malbert, C.-H., Parnet, P., Lallès, J.-P., Segain, J.-P. Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs.

Functional, molecular and genetic neuroimaging has highlighted the existence of brain anomalies and neural vulnerability factors related to obesity and eating disorders such as binge eating or anorexia nervosa. In particular, decreased basal metabolism in the prefrontal cortex and striatum as well as dopaminergic alterations have been described in obese subjects, in parallel with increased activation of reward brain areas in response to palatable food cues. Elevated reward region responsivity may trigger food craving and predict future weight gain. This opens the way to prevention studies using functional and molecular neuroimaging to perform early diagnostics and to phenotype subjects at risk by exploring different neurobehavioral dimensions of the food choices and motivation processes. In the first part of this review, advantages and limitations of neuroimaging techniques, such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), pharmacogenetic fMRI and functional near-infrared spectroscopy (fNIRS) will be discussed in the context of recent work dealing with eating behavior, with a particular focus on obesity. In the second part of the review, non-invasive strategies to modulate food-related brain processes and functions will be presented. At the leading edge of non-invasive brain-based technologies is real-time fMRI (rtfMRI) neurofeedback, which is a powerful tool to better understand the complexity of human brain–behavior relationships. rtfMRI, alone or when combined with other techniques and tools such as EEG and cognitive therapy, could be used to alter neural plasticity and learned behavior to optimize and/or restore healthy cognition and eating behavior. Other promising non-invasive neuromodulation approaches being explored are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS). Converging evidence points at the value of these non-invasive neuromodulation strategies to study basic mechanisms underlying eating behavior and to treat its disorders. Both of these approaches will be compared in light of recent work in this field, while addressing technical and practical questions. The third part of this review will be dedicated to invasive neuromodulation strategies, such as vagus nerve stimulation (VNS) and deep brain stimulation (DBS). In combination with neuroimaging approaches, these techniques are promising experimental tools to unravel the intricate relationships between homeostatic and hedonic brain circuits. Their potential as additional therapeutic tools to combat pharmacorefractory morbid obesity or acute eating disorders will be discussed, in terms of technical challenges, applicability and ethics. In a general discussion, we will put the brain at the core of fundamental research, prevention and therapy in the context of obesity and eating disorders. First, we will discuss the possibility to identify new biological markers of brain functions. Second, we will highlight the potential of neuroimaging and neuromodulation in individualized medicine. Third, we will introduce the ethical questions that are concomitant to the emergence of new neuromodulation therapies., Highlights • We review the neural vulnerability factors related to obesity and eating disorders. • We compare the pros and cons of neuroimaging techniques to study eating behavior. • We present non-invasive strategies to modulate food-related brain processes. • We also present invasive neuromodulation methods such as VNS and DBS. • We discuss about neuroimaging and neuromodulation for prevention and therapy.

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.brs.2017.04.126; International audience; Background :Abdominal bilateral vagal stimulation reduces food intake in animals. However, the classical square wave, mA range current generator is poorly effective to evoke action potentials on A∂ and C neurons that represent the majority of vagal neurons at the abdominal level.Objective/Hypothesis :(i) To ascertain the capability of very high-frequency stimulation schemes (pulsons) to trigger action potentials in abdominal vagal neurons in anaesthetized pigs. (ii) To compare these stimulation schemes with classical ones using PET imaging of brain metabolism and food intake behaviour in conscious pigs.Methods :The current thresholds for pulsons (S2 & S3) and millisecond pulses (S1) required to trigger action potentials were calculated in 5 anaesthetized pigs using single fibre recording. Similar stimulation protocols were compared chronically to sham stimulation in 24 pigs. After two weeks of chronic stimulation, food intake and brain metabolism were investigated. The electrical characteristics and histology of the vagus nerve were also studied.Results :S3 stimulation required a lower amount of charges to trigger an action potential. Chronically applied S2 & S3 activated the dorsal vagal complex and increased the metabolism of its afferent cortical structures. They also reduced energy intake together with a reduced ingestion of high fat and high sugar diets. All these effects were not observed for the S1 group. The vagal histology for the S1, S2 and S3 groups was not different from that of the sham.Conclusions :These findings demonstrate that pulsons applied bilaterally on the abdominal vagus reduced food intake as a consequence of the activation of the brainstem and higher-order brain areas.

This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0847/-/DC1.; Acute vagal stimulation modifies glucose and insulin metabolism, but the effect of chronic bilateral vagal stimulation is not known. Our aim was to quantify the changes in whole body and organ-specific insulin sensitivities, 12 weeks after permanent, bilateral, vagal stimulation performed at the abdominal level in adult mini-pigs. In 15 adult mini-pigs, stimulating electrodes were placed around the dorsal and ventral vagi using laparoscopy and connected to a dual channel stimulator placed subcutaneously. Animals were divided into three groups based on stimulation and body weight i.e. lean non-stimulated, obese non-stimulated and obese-stimulated. Twelve weeks after surgery, glucose uptake and insulin sensitivity were measured using PET during an isoglycemic clamp. Mean whole body insulin sensitivity was lower by 34% (P

National audience; Introduction: A lot of evidences defend the existence of a relationship between a Western diet and the increase of obesity prevalence (OMS, 2011). Particularly, the quality of early nutrition has a long-term impact on the offspring’s phenotype and health status (Barker, 1989). The aim of our study was to explore in the Yucatan minipig model the impact of the maternal diet (High Fat Fructose diet, HFF versus standard diet, STD) during pregnancy and lactation on the cognitive and hedonic functions of the offspring at the adult age, through behavioural assessments and brain imaging, combined with metabolic and physiological explorations. A challenge with an obesogenic diet was then performed to assess its effects on eating behaviour, weight gain and blood parameters.Material & methods: Learning and memory performances were tested using the holeboard discrimination task, with a palatable food reward (M&M’s®), and an Alley maze test, independent from food reward. Eating behaviour was explored with a two-choice feed test and an operant conditioning test with progressive ratio. In parallel, the brain basal glucose metabolism was investigated using Positron Emission Tomography (PET) and the dopaminergic brain reward system (in particular the striatum) was explored using DAT-scan imaging. Biologic samples were collected for blood profiles and analysis of the gut microbiota activity (FFA).Results: We showed that early nutrition could indirectly impact cognitive performances, modulating the emotional status in a high-anxiogenic/low-motivating (maze) situation, but not in low-anxiogenic/high-motivating situation (holeboard). As a matter of fact, STD better succeeded in the maze, whereas no difference appeared during the holeboard test. During the feeding tests, HFF showed a tendency to eat more than STD group. Brain sub-activations in the anterior prefrontal cortex and accumbens nucleus, as well as impairment of the striatal dopaminergic system were observed, which may explain eating behavior differences between HFF and STD. On the other hand, HFF presented better lipids profiles than STD. After an obesogenic challenge, we surprisingly observed that STD ate and gained more weight than HFF, while HFF inflammatory status was higher than STD. Conclusion: All these results suggest that HFF maternal western diet had a deleterious impact on the neurocognitive functions, in a high stressful situation, of the offspring and modulated its responses to an obesogenic dietary challenge.Key words: nutritional imprinting, behavior, brain, reward system, memory, learning, minipigs

National audience; Introduction: A lot of evidences defend the existence of a relationship between a Western diet and the increase of obesity prevalence (OMS, 2011). Particularly, the quality of early nutrition has a long-term impact on the offspring’s phenotype and health status (Barker, 1989). The aim of our study was to explore in the Yucatan minipig model the impact of the maternal diet (High Fat Fructose diet, HFF versus standard diet, STD) during pregnancy and lactation on the cognitive and hedonic functions of the offspring at the adult age, through behavioural assessments and brain imaging, combined with metabolic and physiological explorations. A challenge with an obesogenic diet was then performed to assess its effects on eating behaviour, weight gain and blood parameters.Material & methods: Learning and memory performances were tested using the holeboard discrimination task, with a palatable food reward (M&M’s®), and an Alley maze test, independent from food reward. Eating behaviour was explored with a two-choice feed test and an operant conditioning test with progressive ratio. In parallel, the brain basal glucose metabolism was investigated using Positron Emission Tomography (PET) and the dopaminergic brain reward system (in particular the striatum) was explored using DAT-scan imaging. Biologic samples were collected for blood profiles and analysis of the gut microbiota activity (FFA).Results: We showed that early nutrition could indirectly impact cognitive performances, modulating the emotional status in a high-anxiogenic/low-motivating (maze) situation, but not in low-anxiogenic/high-motivating situation (holeboard). As a matter of fact, STD better succeeded in the maze, whereas no difference appeared during the holeboard test. During the feeding tests, HFF showed a tendency to eat more than STD group. Brain sub-activations in the anterior prefrontal cortex and accumbens nucleus, as well as impairment of the striatal dopaminergic system were observed, which may explain eating behavior differences between HFF and STD. On the other hand, HFF presented better lipids profiles than STD. After an obesogenic challenge, we surprisingly observed that STD ate and gained more weight than HFF, while HFF inflammatory status was higher than STD. Conclusion: All these results suggest that HFF maternal western diet had a deleterious impact on the neurocognitive functions, in a high stressful situation, of the offspring and modulated its responses to an obesogenic dietary challenge.Key words: nutritional imprinting, behavior, brain, reward system, memory, learning, minipigs

Impact of the maternai diet during perinatal period on brain processes, behavior and metabolism of adult Yucatan mini pigs. 3. Colloque de la Société Francophone pour la recherche et l'éducation sur les Origines Développementales, Environnementales et Epigénétiques de la Santé et des Maladies (SF-DOHAD)

International audience; A lot of evidences defend the existence of a relationship between industrial food consumption and the increase of obesity prevalence (OMS, 2011). Our study explored the impact of Western diet exposure on both cognitive and hedonic functions through behavioural assessments and brain imaging, completing by metabolic and physiologic assessment, to determine the role of diet, then, weight gain, on the cognitive abilities, eating behaviour and metabolism of adult males and females Yucatan minipigs, before and after diet induced obesity challenge. Learning and memory performances were tested using the holeboard discrimination task, with a palatable food reward (M&M’s®). Eating behaviour was explored with a two-choice feed test. In parallel, the brain glucose metabolism was investigated using Positron Emission Tomography (PET), during a sucrose oral stimulation. This longitudinal study involves three steps : the first one aims to compare an HFF (hight fat fructose) to a STD (standard) diet, with isocaloric incomes. The second one consisting in an obesogenic challenge with ad libitum access to HFF food. The third step involves weight loss, using bariatric surgery or restrained diet. Key words: nutritional imprinting, behavior, brain, reward system, memory, learning, minipigs

International audience

Obesity-associated alterations of glucose metabolism are ameliorated after chronic stimulation of abdominal vagus nerve

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International audience; Excessive sugar intake might increase the risk to develop eating disorders via an altered reward circuitry, but it remains unknown whether different sugar sources induce different neural effects and whether these effects are dependent from body weight. Therefore, we compared the effects of three high-fat and isocaloric diets varying only in their carbohydrate sources on brain activity of reward-related regions, and assessed whether brain activity is dependent on insulin sensitivity. Twenty-four minipigs underwent 18FDG PET brain imaging following 7-month intake of high-fat diets of which 20% in dry matter weight (36.3% of metabolisable energy) was provided by starch, glucose or fructose (n = 8 per diet). Animals were then subjected to a euglycemic hyperinsulinemic clamp to determine peripheral insulin sensitivity. After a 7-month diet treatment, all groups had substantial increases in body weight (from 36.02±0.85 to 63.33±0.81 kg; P

International audience; Objective. Neural signals along the vagus nerve (VN) drive many somatic and autonomic functions. The clinical interest of VN stimulation (VNS) is thus potentially huge and has already been demonstrated in epilepsy. However, side effects are often elicited, in addition to the targeted neuromodulation. Approach. This review examines the state of the art of VNS applied to two emerging modulations of autonomic function: heart failure and obesity, especially morbid obesity. Main results. We report that VNS may benefit from improved stimulation delivery using very advanced technologies. However, most of the results from fundamental animal studies still need to be demonstrated in humans.

AniMate - An open source software for absolute PET quantification. Annual congress of the european association of nuclear medicine

International audience; Uncoupling between striatal dopamine transporter and glucose metabolism in diet induced obesity. 27th International Symposium on Cerebral Blood Flow, Metabolism and Function / 12th International Conference on Quantification of Brain Function with PET

International audience; Objectives: The characterization of brain networks contributing to the processing of oral and/or intestinal sugar signals in a relevant animal model might help to understand the neural mechanisms related to the control of food intake inhumans and suggest potential causes for impaired eating behaviours. The aims of this study were 1) to investigate whether the combination or dissociation between oral and post-oral sucrose perception influence the brain activity in reward-related brain structures, and 2) to determine whether duodenal infusion of sucrose in the absence of sweet taste, and conversely, induce specific activity in the brain reward circuit. Methods: Seven growing pigs underwent four brain single photon emission computed tomography to assess cerebral bloodflow (CBF) modifications further to oral stimulation with neutral or sucrose artificial saliva paired with saline or sucrose infusion in the duodenum. For each brain imaging session, animals were anaesthetised after an overnight fasting and the injection of 99Tc-HMPAO (740 MBq) was synchronized with the oral stimulation, 50 min after the duodenal infusion (timeline corresponding to the peak of glycemia after sucrose duodenal infusion). CBF changes were investigated via SVC analyses using SPM8 in several regions of interest including cortical and subcortical areas of the hedonic/limbic circuit. An uncorrected value of P=0.01 was set as threshold for the clusters’ peak and clusters comprising a minimum of 25 contiguous voxels were considered significant.Results: Oral and/or duodenal sucrose sensing induced differential CBF changes in brain regions known to be involved in memory, reward processes and hedonic (i.e. pleasure) evaluation of sensory stimuli, including the dorsal striatum,prefrontal cortex, cingulate cortex, insular cortex, hippocampus, and parahippocampus cortex. Sucrose duodenal infusion only and combined sucrose stimulation induced similar activity patterns in the putamen, ventral anterior cingulate cortex and hippocampus. Some brain deactivations in the prefrontal and insular cortices were onlydetected in the presence of oral sucrose stimulation.Finally, activation of the right insular cortex was only induced by combined oral and duodenal sucrose stimulation, while specific activity patterns were detected in the hippocampus and parahippocampal cortex with oral sucrose dissociated from caloric load.Conclusions: We demonstrated that oral, duodenal and the bimodal perception of sucrose induced different patterns of brain metabolism in structures involved in memory, reward processes and hedonic evaluation of sensory stimuli. Using controlled conditions in a pertinent animal model for human nutrition and nutrient sensing, we managed to demonstrate that some CBF changes are specific to oralor duodenal sucrose sensing, and that bimodal sucrose stimulation can even have a synergetic effect in some brain areas. We identified brain areas that are probably involved in the congruence between the sweet oral perceptionand internal state. All these results have important implications for discussions related to caloric vs. non-caloric sweeteners consumption and impact of sugars on the brain hedonic circuits and motivational processes.

Événement(s) lié(s) : - (NER); International audience; This paper describes the fabrication and the packaging of a flexible parylene-based multi-contact electrode embedded in a silicone-based cuff. This type of electrode is well suited for peripheral nerve recording and offers improved spatial selectivity. We conducted mechanical and electrical tests for assessing the reliability by using an accelerated lifetime protocol. Test structures made with platinum sandwiched with parylene C were designed. The accelerated lifetime soaking tests in phosphate buffered saline (PBS) solution at 67 degrees C showed a longer life time (approximatively 4.5 years) with a dehydration bake introduction in the process flow and a parylene thickness increase. A specific test bench was developed for the mechanical cycling and for evaluating the mechanical robustness of the thin film devices.

International audience; Vagal nerve activity has been shown to be impacted in the case of Heart Failure. A direct recording of vagal nerve activity could be useful to investigate its characteristics, especially in the case of the vagal nerve stimulation therapy, which has been shown to be useful in heart failure patients. The objective of this paper is to validate the measurement of vagal nerve activity in a heart failure sheep model and to examine its characteristics and relationships with other cardiovascular parameters. Three sheep were implanted with an electrode on the right cervical vagus nerve and nervous activity were recorded together with left ventricular pressure and intraventricular electrocardiogram. Baseline periods showed fluctuations of vagal activity at the respiratory rate, correlated with fluctuations of ventricular pressure. Those fluctuations disappeared after a distal section of the nerve. Valsalva-like manoeuvres were induced in the sheep, and nervous activity was raised during the continuous positive pressure and lowered during the apnea. Another experiment on a pig also showed that the modifications of vagal activity during a Valsalva were suppressed by the application of the local anaesthesia xylocaine.

International audience; The voltage required to stimulate small diameter myelinated (Adelta fibres) and unmyelinated (C fibres) neurons consistently is so large that it is unsafe for chronic vagal stimulation. We present here a solution that reduces by 80% the amount of electrical charge necessary to produce action potential. These solutions were tested in a porcine model that allowed simultaneously to locate the origin of the afferent neurons, to stimulate the vagal trunks at distance from the recording electrode and to record the evoked activity of one neuron using the single afferent method. The reduction in current supplied by the most effective pulse pattern makes possible to incorporate this solution in an implanted device without damaging the vagal nerve.

International audience; Background Substantial increases in dietary sugar intake together with the increasing prevalence of obesity worldwide, as well as the parallels found between sugar overconsumption and drug abuse, have motivated research on the adverse effects of sugars on health and eating behaviour. Given that the gut-brain axis depends on multiple interactions between peripheral and central signals, and because these signals are interdependent, it is crucial to have a holistic view about dietary sugar effects on health. Methods Recent data on the effects of dietary sugars (i.e. sucrose, glucose, and fructose) at both peripheral and central levels and their interactions will be critically discussed in order to improve our understanding of the effects of sugars on health and diseases. This will contribute to the development of more efficient strategies for the prevention and treatment for obesity and associated co-morbidities. Results This review highlights opposing effects of glucose and fructose on metabolism and eating behaviour. Peripheral glucose and fructose sensing may influence eating behaviour by sweet-tasting mechanisms in the mouth and gut, and by glucose-sensing mechanisms in the gut. Glucose may impact brain reward regions and eating behaviour directly by crossing the blood-brain barrier, and indirectly by peripheral neural input and by oral and intestinal sweet taste/sugar-sensing mechanisms, whereas those promoted by fructose orally ingested seem to rely only on these indirect mechanisms. Conclusions Given the discrepancies between studies regarding the metabolic effects of sugars, more studies using physiological experimental conditions and in animal models closer to humans are needed. Additional studies directly comparing the effects of sucrose, glucose, and fructose should be performed to elucidate possible differences between these sugars on the reward circuitry.

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International audience; The characterization of brain networks contributing to the processing of oral and/or intestinal sugar signals in a relevant animal model might help to understand the neural mechanisms related to the control of food intake in humans and suggest potential causes for impaired eating behaviors. This study aimed at comparing the brain responses triggered by oral and/or intestinal sucrose sensing in pigs. Seven animals underwent brain single photon emission computed tomography ((99m)Tc-HMPAO) further to oral stimulation with neutral or sucrose artificial saliva paired with saline or sucrose infusion in the duodenum, the proximal part of the intestine. Oral and/or duodenal sucrose sensing induced differential cerebral blood flow changes in brain regions known to be involved in memory, reward processes and hedonic (i.e., pleasure) evaluation of sensory stimuli, including the dorsal striatum, prefrontal cortex, cingulate cortex, insular cortex, hippocampus, and parahippocampal cortex. Sucrose duodenal infusion only and combined sucrose stimulation induced similar activity patterns in the putamen, ventral anterior cingulate cortex and hippocampus. Some brain deactivations in the prefrontal and insular cortices were only detected in the presence of oral sucrose stimulation. Finally, activation of the right insular cortex was only induced by combined oral and duodenal sucrose stimulation, while specific activity patterns were detected in the hippocampus and parahippocampal cortex with oral sucrose dissociated from caloric load. This study sheds new light on the brain hedonic responses to sugar and has potential implications to unravel the neuropsychological mechanisms underlying food pleasure and motivation.

International audience; Introduction The aim of this study was to assess whether chronic intake of isocaloric high-fat diets differing partly in the source of carbohydrates (starch, glucose or fructose) and fed at the same level of intake impacts eating behaviour in the adult Yucatan minipig. Methods Adult minipigs were offered for 8 weeks either of three high-fat diets in which 20% of dry matter weight (36.3% of metabolizable energy) was provided as pure maize starch (SD), glucose (GD) or fructose (FD) (n = 5 per diet). Three eating behaviour tests, including a three-feed choice test, an eating microstructure test and operant conditioning with progressive ratio test were performed before and after dietary treatment in order to evaluate the impact of these carbohydrates on feed preferences and animal's motivation. Results After 8-week treatment, all groups had similar increases in body weight (from 36.2 ± 1.2 to 57.5 ± 0.1 kg, P < 0.0001). Animals showed initial preference and higher motivation for the GD over the SD, FD being intermediate. Importantly, only pigs chronically fed the FD developed a large preference for this diet: increase in FD intake (from 15 ± 3 to 35 ± 6 g/kg0.75, P < 0.05). After 8 weeks of experimental diets, intake speed of FD (19 ± 6 g/min) was higher compared to GD and SD (P = 0.001). Conclusion Our data indicate that chronic intake of diets differing in a part of the carbohydrate source induced substantial weight gain, regardless of the carbohydrate source. Pigs’ initial preference and higher motivation was for the GD, compared to SD and FD. Intake of the fructose-containing diet for 8 weeks induced a stronger preference for this diet. Our data may have important implications in terms of impact of prolonged fructose consumption on eating behaviour in humans.