Neuroimaging and neuromodulation approaches to study eating behavior and prevent and treat eating disorders and obesity.

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.

Using encapsulated freeze-dried lipids to trigger a gastrointestinal vagal reflex: validation in a pig model.

BACKGROUND: Nutrient-sensing studies in humans frequently use intragastric intubation. A non-invasive alternative would be the use of freeze-dried lipids (FDL) capsules. We proposed to validate this method in pigs by (i) demonstrating that low-dose FDL can increase vagal activity, gastric compliance (GC), and delay gastric emptying time (GET); (ii) evaluating the release kinetics of encapsulated FDL. METHODS: Nine conscious pigs fitted with duodenal catheter and gastric cannula were administered FDL (3-mL freeze-dried Intralipid(®) ). Vagal tone was estimated via heart rate variability (HRV) measurements, GC was measured via the barostatic method, and GET after a test meal was evaluated via scintigraphy. FDL vs placebo (methylcellulose [MC]) capsules release kinetics were also evaluated via scintigraphy. KEY RESULTS: Duodenal FDL infusion increased GC in 2/8 trials only, but systematically delayed GET compared to saline (96 vs 70 min; p = 0.018). The presence of FDL in the duodenum decreased heart rate, increased vagal tone, and HRV. FDL capsules released their content in the duodenum before MC capsules (41 vs 67 min; p = 0.013), and MC induced ECG data quite similar to FDL except for HRV (p = 0.011). CONCLUSIONS & INFERENCES: Low-dose FDL was a potent signal to induce vagal reflex and increase GET. FDL capsules released their content in the duodenum and activated the vagal pathway after approximately 40 min, which is an important data for designing future paradigms in humans. MC was not a good placebo because of its stickiness and ability to activate the vagal pathway too.

Brain processing of duodenal and portal glucose sensing.

Peripheral and central glucose sensing play a major role in the regulation of food intake. Peripheral sensing occurs at duodenal and portal levels, although the importance of these sensing sites is still controversial. The present study aimed to compare the respective influence of these sensing pathways on the eating patterns; plasma concentrations of glucose, insulin and glucagon-like peptide-1 (GLP-1); and brain activity in juvenile pigs. In Experiment 1, we characterised the changes in the microstructure as a result of a 30-min meal in eight conscious animals after duodenal or portal glucose infusion in comparison with saline infusion. In Experiment 2, glucose, insulin and GLP-1 plasma concentrations were measured during 2 h after duodenal or portal glucose infusions in four anaesthetised animals. In Experiment 3, single photon emission computed tomography brain imaging was performed in five anaesthetised animals receiving duodenal or portal glucose or saline infusions. Both duodenal and portal glucose decreased the amount of food consumed, as well as the ingestion speed, although this effect appeared earlier with the portal infusion. Significant differences of glucose and GLP-1 plasma concentrations between treatments were found at the moment of brain imaging. Both duodenal and portal glucose infusions activated the dorsolateral prefrontal cortex and primary somatosensory cortex. Only duodenal glucose infusion was able to induce activation of the prepyriform area, orbitofrontal cortex, caudate and putamen, as well as deactivation of the anterior prefrontal cortex and anterior entorhinal cortex, whereas only portal glucose infusion induced a significant activation of the insular cortex. We demonstrated that duodenal and portal glucose infusions led to the modulation of brain areas that are known to regulate eating behaviour, which probably explains the decrease of food intake after both stimulations. These stimulation pathways induced specific systemic and central responses, suggesting that different brain processing matrices are involved.

Comparison of gizzard activity between chickens from genetic D+ and D- lines selected for divergent digestion efficiency.

Gizzard motility was compared between chickens from D(+) (high digestion efficiency) and D(-) (low digestion efficiency) genetic lines selected for divergent digestion efficiency, using strain gauge transducers. Motility was recorded continuously during 24 h in 6 birds per line. Two stimuli, a meal distribution after a feed-deprivation period and lighting after a dark period, were tested during the recording period. A functional test with intravenous injection of serotonin performed at the end of the recording day often resulted in a sharp reduction in gizzard motility, without a significant difference between lines. Compared with D(+) birds, gizzard activity in D(-) birds remained high during fasting or dark periods (P < 0.0006), which reduced the effects of stimuli in D(-) birds. So, coordination between bird activity and gizzard motility tended to be reduced in D(-) compared with D(+) birds (P = 0.0018). This coordination was observed to be positively correlated (P = 0.011) with the relative weight (g/kg of BW) of the stomach (gizzard + proventriculus). This experiment pointed out differences in gizzard motility between D(+) and D(-) chicken lines in terms of response to environmental stimuli, characterized by a failure in the gizzard relaxation process in D(-) birds during rest periods.

Flavour exposures after conditioned aversion or preference trigger different brain processes in anaesthetised pigs.

We describe the behavioural consequences of conditioned flavour aversion and preference in pigs and have investigated the brain circuits involved in the representation of flavours with different hedonic values. The study was performed on eight 30-kg pigs. (i) Animals were negatively conditioned to an F- flavour added to a meal followed by LiCl intraduodenal (i.d.) injection, and positively conditioned to an F+ flavour added to a meal followed by NaCl i.d. injection. F+ and F- were thyme or cinnamon flavours. After each conditioning, the behavioural activities were recorded; (ii) One and 5 weeks later, animals were subjected to three two-choice food tests to investigate their preferences between F+, F- and a novel flavour (O); and (iii) Anaesthetised animals were subjected to three SPECT brain imaging sessions: control situation (no flavour) and exposure to F+ and to F-. The negative reinforcement induced a physical malaise and visceral illness. After a positive reinforcement, animals showed playing or feeding motivation and quietness. F+ was significantly preferred over O and F-, and O was significantly preferred over F-. Both F- and F+ induced some metabolic differences in neural circuits involved in sensory associative processes, learning and memory, emotions, reward and feeding motivation. Exposure to F+ induced a higher activity in corticolimbic and reward-related areas, while F- induced a deactivation of the basal nuclei and limbic thalamic nuclei. This study reveals the unconscious cognitive dimension evoked by food flavours according to the individual experience, and highlights the importance of the food sensory image on hedonism and anticipatory eating behaviour.

Slower eating rate is independent to gastric emptying in obese minipigs.

The aim of our study was to investigate whether the altered eating behavior observed in the context of a diet-induced metabolic syndrome is related to changes of the gastric emptying and autonomic balance. Eight adult male Göttingen minipigs were subjected during 5months to ad libitum Western diet (WD). Several factors were compared between the lean (before WD) and obese conditions: general activity and eating behavior, gastric emptying, adiposity, glycemia and insulinemia during IVGTT, and heart rate variability (HRV). In our model, obesity did not alter the gastric emptying (258±26 vs. 256±14 min, P>0.10) but induced insulin resistance: increased basal insulinemia (12.6±0.8 to 36.6±6.1 mU/l, P<0.02) and reduced insulin sensitivity (4.5E-4±0.7E-4 to 2.5E-4±0.2E-4 min(-1) per mU.l(-1) of insulin, P<0.05). The HRV and sympathovagal balance were not significantly modified (P>0.10). Fed ad libitum with WD, animals overate durably (P<0.001). During a 30-min meal test though, the ingestion speed, the food ingested (1076±48 vs. 520±52 g) and energy intake decreased in the obese condition (P<0.05), which can be explained by the fragmentation of the daily caloric intake. These data suggest that the slower eating rate and increased number of meals observed in obese minipigs without neuropathy is independent to gastric emptying. The explanation may be sought rather in central modifications induced by obesity that might modify the food perception and/or motivation.

Chronic vagus nerve stimulation decreased weight gain, food consumption and sweet craving in adult obese minipigs.

Chronic vagus nerve stimulation (VNS) is known to influence food intake and body weight in animals and humans. The aim of our work was to evaluate the effects of long-term VNS in adult obese minipigs. Eight minipigs were fed ad libitum a Western diet to cause obesity, after which half of the animals were implanted with bilateral vagal electrodes connected to constant current stimulators (2mA, 30Hz, 500-µs pulse, ON 30s, OFF 5min). The other animals were implanted with sham devices. Animals were weighed weekly and their daily consumption was measured. Still 14 weeks after surgery, VNS animals (70.3±3.3kg, P>0.10) did not significantly gain weight compared to sham animals (80.6±8.0kg, P<0.05). Furthermore, food consumption decreased in VNS animals (-18%, P<0.02) compared to sham animals (+1%, P>0.10). When subjected to a three-choice meal test (high-fat vs. high-carbohydrates vs. balanced diet), VNS animals decreased their sweet-food consumption compared to sham animals (P<0.05), and increased their balanced diet consumption in comparison to pre-surgery levels. Our results showed that chronic VNS decreased weight gain, food consumption and sweet craving in adult obese minipigs, which indicates that this therapy might be used to decrease appetite in the context of morbid obesity.

A computed tomography scan application to evaluate adiposity in a minipig model of human obesity.

The aim of the present study was to describe and validate a computed tomography (CT) method to analyse adiposity distribution in Göttingen minipigs. Adiposity was evaluated in two groups of minipigs. In group 1 (n 8), measurements were performed before and after the induction of obesity. In group 2 (n 7), animals were fed rations designed to obtain heterogeneous adiposity before analyses. CT acquisitions were associated with anatomical, ultrasonography and body chemical measurements. Our CT method was based on acquisition of a single slice at a fixed anatomical landmark, calculation of individual X-ray density ranges for CT values and delineation of the three main adipose compartments (subcutaneous adipose tissue, SAT; retroperitoneal adipose tissue, RAT; and visceral adipose tissue, VAT). Our validation measures showed that the CT-scan method was accurate, sensitive and reliable. The CT data were found to be correlated with body weight, abdominal perimeter, ultrasonography, anatomical measurements and body chemical composition (from r 0.84 to 0.93, P < 0.001 for all), with a pitfall concerning the precise estimation of VAT. With increased body weight, the amount of adipose tissue increased and the relative proportion of SAT increased, whereas the relative proportion of RAT and VAT decreased (P < 0.001 for all). Adiposity measured by CT, and especially SAT, was found to be negatively correlated with insulin sensitivity (r 0.54, P < 0.05). In conclusion, a precise evaluation of the adipose compartments in minipigs was done by CT. Therefore, the use of Göttingen minipigs is relevant to further investigate the relationship between the different adipose tissues and obesity.

Gastric tone, volume and emptying after implantation of an intragastric balloon for weight control.

BACKGROUND: The intragastric balloon, filled with air or liquid is used before elective bariatric surgery because its efficacy is limited. This might be the consequence of altered gastric functions. Therefore, we aimed to investigate, in an animal model, the changes in gastric motility and emptying induced by long-term insertion of a balloon used for weight reduction. METHODS: Ten Göttingen mini-pigs were allocated into two groups with and without an intragastric balloon for 5 months. Balloons were inserted under endoscopy during general anesthesia and were filled with 350 mL of air. Gastric emptying was evaluated by scintigraphy. Gastric volume was measured by single photon emission computed tomography and proximal gastric compliance obtained using an electronic barostat. Changes in vagal tone were assessed by heart rate variability (HRV). KEY RESULTS: After balloon insertion, gastric volume was significantly increased (2047 +/- 114.8 cm(3) after vs 1674 +/- 142.5 cm(3) before insertion, P < 0.05). Gastric compliance was also larger in balloon group (219 +/- 23.4 mL mmHg(-1) in balloon vs 168 +/- 7.7 mL mmHg(-1) in control group). Gastric emptying was reduced after insertion of the balloon (T(1/2) = 204 +/- 28.8 min vs 159 +/- 25.4 before vs after insertion). High frequency components of the spectral analysis of HRV, representing vagal tone, were increased in balloon group. CONCLUSIONS & INFERENCES: The proximal stomach was enlarged after the insertion of a balloon in the stomach as a consequence of an increased gastric compliance. This change in compliance was probably causative for a reduction in gastric emptying rate of solids. These alterations were associated with increased vagal tone.

Subthalamic nucleus stimulation in Parkinson disease induces apathy: a PET study.

OBJECTIVE: Apathy may be induced by subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease (PD). We therefore wished to test the hypothesis that apathy induced by STN-DBS correlates with changes in glucose metabolism, using (18)FDG-PET. METHODS: Twelve patients with PD were assessed 3 months before (M-3) and 3 months after (M+3) STN-DBS with (18)FDG-PET and the Apathy Evaluation Scale. RESULTS: Apathy had significantly worsened at M+3 after STN-DBS. Positive correlations were observed between this variation in apathy scores and changes in glucose metabolism, especially in the right frontal middle gyrus (Brodmann area [BA] 10) and right inferior frontal gyrus (BA 46 and BA 47). Negative correlations between the two were observed in the right posterior cingulate gyrus (BA 31) and left medial frontal lobe (BA 9). CONCLUSION: These preliminary results confirm the role of the subthalamic nucleus in associative and limbic circuitry in humans and suggest that it is a key basal ganglia structure in motivation circuitry.

The pig model in brain imaging and neurosurgery.

The pig model is increasingly used in the field of neuroscience because of the similarities of its brain with human. This review presents the peculiarities of the anatomy and functions of the pig brain with specific reference to its human counterpart. We propose an approximate mapping of the pig's cortical areas since a comprehensive description of the equivalent of Brodmann's areas is lacking. On the contrary, deep brain structures are received more consideration but a true three-dimensional (3D) atlas is still eagerly required. In the second section, we present an overview of former works describing the use of functional imaging and neuronavigation in the pig model. Recently, the pig has been increasingly used for molecular imaging studies using positron emission tomography (PET). Indeed, the large size of its brain is compatible with the limited spatial resolution of the PET scanner built to accommodate a human being. Similarly, neuronavigation is an absolute requirement to target deep brain areas in human and in pig since the surgeon cannot rely on external skull structures for zeroing the 3D reference frame. Therefore, a large body of methodological refinements has been dedicated to image guided surgery in the pig model. These refinements allow now a millimetre precision: an absolute requirement for basal nuclei targeting. In the third section, several examples of ongoing studies in our laboratory were presented to illustrate the intricacies of using the pig model. For both examples, after a brief description of the scientific context of the experiment, we present, in detail, the methodological steps required to achieve the experimental goals, which are specific to the porcine model. Finally, in the fourth section, the anatomical variations depending on the breed and age are discussed in relation with neuronavigation and brain surgery. The need for a digitized multimodality brain atlas is also highlighted.

Subthalamic nucleus stimulation affects orbitofrontal cortex in facial emotion recognition: a PET study.

Deep brain stimulation (DBS) of the bilateral subthalamic nucleus (STN) in Parkinson's disease is thought to produce adverse events such as emotional disorders, and in a recent study, we found fear recognition to be impaired as a result. These changes have been attributed to disturbance of the STN's limbic territory and would appear to confirm that the negative emotion recognition network passes through the STN. In addition, it is now widely acknowledged that damage to the orbitofrontal cortex (OFC), especially the right side, can result in impaired recognition of facial emotions (RFE). In this context, we hypothesized that this reduced recognition of fear is correlated with modifications in the cerebral glucose metabolism of the right OFC. The objective of the present study was first, to reinforce our previous results by demonstrating reduced fear recognition in our Parkinson's disease patient group following STN DBS and, second, to correlate these emotional performances with glucose metabolism using (18)FDG-PET. The (18)FDG-PET and RFE tasks were both performed by a cohort of 13 Parkinson's disease patients 3 months before and 3 months after surgery for STN DBS. As predicted, we observed a significant reduction in fear recognition following surgery and obtained a positive correlation between these neuropsychological results and changes in glucose metabolism, especially in the right OFC. These results confirm the role of the STN as a key basal ganglia structure in limbic circuits.

Reduced mechanosensitivity of duodenal vagal afferent neurons after an acute switch from milk-based to plant-based diets in anaesthetized pigs.

Acute changes in diet composition and/or origin alter gastric emptying and gastrointestinal motility. One of the hypotheses explaining these alterations involves changes in the sensitivity of duodenal vagal sensory neurons. The aim of this study was to evaluate the characteristics of multimodal duodenal vagal sensory neurons in 20 pigs feed either with milk-based or plant-based diets of identical caloric content. Twenty duodenal vagal afferents were recorded in anesthetized animal from the cervical vagus using the single fiber method. 10 pigs were fed with a milk-based diet (MD) for one month while the diet of the 10 other pigs was changed for plant-based diet (PD) the day preceding the recording session. The behavior of the receptors was tested in basal resting conditions and after challenges with duodenal intralipid and close intra-arterial injection of CCK, 5-HT or capsaicin with and without isovolumetric duodenal distensions at 20, 40 and 60 mmHg. All receptors were slowly adapting C type fiber with a receptor field located 6-7 cm distal to the pylorus. The rate of discharge during distension (20, 40 and 60 mmHg) combined with duodenal intralipid was significantly larger for MD compared with PD. Similarly, the rate of discharge observed during distensions performed with CCK and with 5-HT were greater for MD compared with PD while CCK and 5-HT without distension were equally stimulating for MD and PD. No significant difference was found between groups during capsaicin infusion irrespective of the stimulating pressure. In conclusion, a switch to plant-based diet, when compared to a milk-based diet, results in an overall decrease in mechanical sensitivity of duodenal neurons during lipid, 5HT and CCK challenges, but not in basal conditions or after capsaicin. This reduced sensitivity to distension may explain the diet-induced alteration of gastric emptying that is controlled primarily through a vago-vagal reflex.

Involvement of NO in gastric emptying of semi-solid meal in conscious pigs.

The influence of non-selective nitric oxide synthase (NOS) inhibition on gastric emptying of a semi-solid meal was studied in conscious pigs. Antroduodenal motility and fundic compliance were also assessed to evaluate the mechanisms at the origin of potential alteration in gastric emptying pattern. N(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg kg(-1) i.v.) delayed gastric emptying (half-emptying time of 128.98 +/- 16.86 min vs 73.74 +/- 7.73 min after saline, P < 0.05, n = 6) as a result of decreased proximal gastric emptying. No changes were observed for distal gastric emptying as a result of unchanged antral motility. Similarly, no changes were noted on duodenal motor patterns either in the fasted or in the fed state. L-NAME decreased fundic compliance in fasted state (49 +/- 11 mL mmHg(-1) vs 118 +/- 15 mL mmHg(-1) after saline, P < 0.05, n = 6). As this phenomenon is expected to increase emptying rate, the gastroparesis induced by NOS inhibition is thus likely to originate from distal resistive forces. It is concluded that NO positively modulates gastric emptying.

The ileocolonic sphincter.

The human ileocolonic sphincter (ICS) develops a sustained tone mainly due to propagated and not propagated phasic motor activity. The ileocaecocolonic segment is also able to behave, yet uncommonly, as a synchronized segment involving propagated contractions originating from the ileum and migrating to the proximal colon. The ICS motor activity alone has a limited role towards forward flow. On the contrary, the functional entity corresponding to the distal ileum and the ICS provides a clearance mechanism for reflux of colonic contents into the small intestine. The presence of short chain fatty acids (SCFA) in the distal ileum, sensed either by endocrine cells or chemo-sensitive vagal afferents, is an important actor in triggering this clearance mechanism. The ICS tone is in part myogenic but a neuronal nitrergic component is also involved. Reflex excitatory and inhibitory responses of the ICS originating from ileal or colonic distension involve primarily spinal nitrergic and adrenergic pathways.

Human duodenal phase III migrating motor complex activity is predominantly antegrade, as revealed by high-resolution manometry and colour pressure plots.

Abstract Late phase III migrating motor complex activity has been said to be primarily retroperistaltic but has not been assessed with high resolution manometry or three-dimensional colour pressure plots (pressure/time/distance). Duodenal phase III was examined in healthy young volunteers (seven male, two female) with a 20-lumen assembly. With the most proximal sidehole in the distal antrum, after a 4.5-cm interval 18 sideholes at 1.5-cm intervals spanned the duodenum with a final sidehole 3 cm beyond. Fasting pressures were recorded until phase III occurred. Comparisons were made between proximal (P) and distal (D) duodenum during early (E) (first 0.5-1 min) and late (L) (last 0.5-1 min) phase III. With colour pressure analysis, 121 of 180 pressure wave (PW) sequences were purely antegrade, two purely retrograde and 57 bidirectional. Ten of fifty-seven bidirectional PW sequences were complex, branching to become two separate sequences. Bidirectional sequences occurred more frequently in late than early phase III (L 43 vs. E 14 of 57), but their occurrence did not differ between proximal and distal duodenum (P31 vs. D 24 of 57). Antegrade propagation velocity was faster in late compared with early phase III (L 28.50 vs. E 17.05 mm s(-1); P = 0.006), but did not differ between proximal and distal duodenum. Colour pressure analysis also indicated an intermittent segmental pattern to phase III, with each subject exhibiting a change in velocity or direction, or a relative failure of peristalsis somewhere along the duodenum during part of phase III. Duodenal phase III is not homogenous and, in contrast with previous studies, does not primarily constitute a retroperistaltic pump. Colour pressure analysis is useful in interpreting intraluminal pressure profiles and may improve the sensitivity and specificity of clinical studies.

Antropyloroduodenal, cholecystokinin and feeding responses to pulsatile and non-pulsatile intraduodenal lipid infusion.

The contribution of the pulsatile nature of gastric emptying to small intestinal feedback mechanisms modulating antropyloroduodenal motility and appetite is unknown. On separate days, eight healthy male volunteers (18-34 years) received randomized, single-blind, intraduodenal (ID) infusions of 10% Intralipid (2 kcal min(-1)), either continuously [CID], or in a pulsatile manner [PID] (5 s on/15 s off) and 0.9% saline (control) administered continuously, each at a rate of 1.8 mL min(-1) for 3 h. During each infusion, subjective ratings of appetite were assessed and antropyloroduodenal pressures recorded with a 16-lumen manometric assembly incorporating a pyloric sleeve sensor. Plasma cholecystokinin was measured from blood collected at regular intervals throughout the infusion. At the end of each infusion the manometric assembly was removed, subjects were offered a buffet meal and the energy and macronutrient content of the meal was measured. Both ID lipid infusions stimulated isolated pyloric pressure waves (IPPWs) (P < 0.001) and basal pyloric pressure (P < 0.01) and suppressed antral (P < 0.05) and duodenal (P < 0.05) pressure waves when compared to controls; there was no difference in the effects of CID and PID lipid on antropyloroduodenal pressures. Infusions of lipid significantly increased plasma CCK concentrations (P < 0.05) compared with saline, but concentrations were not different between the two modes of lipid delivery (P > 0.05, CID vs. PID). Both intraduodenal lipid infusions decreased hunger (P < 0.05), increased fullness (P < 0.05) and reduced energy intake (P < 0.05) when compared with controls; again there was no difference between CID and PID lipid. We conclude that at the infusion rate of similar 2 kcal min(-1), the acute effects of intraduodenal lipid on antropyloroduodenal pressures, plasma CCK concentration and appetite are not modified by a pulsatile mode of lipid delivery into the duodenum.

The vagus is inhibitory of insulin secretion under fasting conditions.

The involvement of the vagus in the insulin response during the early phase of absorption of a meal has been demonstrated recently. The extent of this vagal influence was investigated during fasting in an anesthetized porcine model. Portal and systemic insulin were evaluated together with glycemia during cooling and sectioning of both cervical vagal trunks in 12 splanchnicotomized or sham-operated pigs. In sham-operated animals, portal and systemic insulin were significantly and reversibly increased by cooling (173 and 123%, respectively). Portal insulin peaked 20 min after the onset of cooling but declined slowly while cooling was still activated. In contrast, systemic insulin was increased evenly along cooling. Section of the vagus was also associated with a portal and systemic insulin increase (144 and 117%) but to a lesser extent than cooling. In both treatments, portal and systemic insulin increases were either reduced (vagal cooling) or eliminated (vagal section) in splanchnicotomized animals. We conclude that the vagus exerts an inhibitory activity on interdigestive insulin secretion that is partly mediated by the splanchnic nerves.

Desensitization of ileal vagal receptors by short-chain fatty acids in pigs.

Coloileal reflux episodes trigger specialized ileal motor activities and inhibit gastric motility in pigs. The initiation of these events requires the detection by the distal ileum of the invading colonic contents that differ from the ileal chyme primarily in short-chain fatty acid (SCFA) concentrations. In addition to the already described humoral pathway, this detection might also involve ileal vagal afferents. Sensitivity to SCFA of 12 ileal vagal units was investigated in anesthetized pigs with single-unit recording at the left cervical vagus. SCFA mixtures (0.35, 0.7, and 1.4 mol/l) containing acetic, propionic, and butyric acids in proportions identical to that in the porcine cecocolon were compared with isotonic and hypertonic saline. All units behaved as slowly adapting mechanoreceptors (half-adaptation time = 35.4 +/- 15.89 s), and their sensitivity to local mechanical probing was suppressed by local anesthesia; 7 units significantly decreased their spontaneous firing with 0.7 and 1.4 but not 0.35 mol/l SCFA infusion compared with hypertonic or isotonic saline. Similarly, the response induced by distension in the same seven units was reduced (5 neurons) or abolished (2 neurons) after infusion of 0.7 (22.8 +/- 2.39 impulses/s) and 1.4 (30.3 +/- 2.12 impulses/s) mol/l SCFA solutions compared with isotonic saline (38.6 +/- 4.09 impulses/s). These differences in discharge were not the result of changes in ileal compliance, which remained constant after SCFA. In conclusion, SCFA, at concentrations near those found during coloileal reflux episodes, reduced or abolished mechanical sensitivity of ileal vagal afferents.

Changes in intragastric meal distribution are better predictors of gastric emptying rate in conscious pigs than are meal viscosity or dietary fibre concentration.

The effect of dietary fibre on the gastric emptying rate of solids is controversial. Similarly, the mechanisms by which it modulates food intake are partially unknown. Gastric emptying and proximal v. distal stomach filling were evaluated in triplicate on four conscious pigs using scintigraphic imaging. Each animal received in an isoenergetic manner a concentrate low-fibre diet enriched in starch (S) and two high-fibre diets based on sugar beet pulp (BP) or wheat bran (WB). All meals had the same viscosity before ingestion (100.0-100.5 Pa.s). Viscosity of the gastric contents was measured in four additional animals fitted with a gastric cannula. The gastric emptying rate of BP diet was significantly slower than S and WB diets (t1/2 78.4 (sem 5.68), 62.8 (sem 10.01) and 111.6 (sem 10.82) min for S, WB and BP diets respectively, P<0.05). For BP diet only, rate of distal stomach filling was steady during the first 120 min after the meal whereas that of S and WB diets decreased in an exponential manner. Numerous backflow episodes from the distal into the proximal stomach were observed for BP diet that generated the larger intragastric viscosity (0.26 (sem 0.03), 0.3 (sem 0.02) and 0.52 (sem 0.002) Pa.s for S, WB and BP respectively). In conclusion, viscosity of the meal or the percentage total fibre, unlike viscosity of the gastric contents, are poor predictors for emptying. The reduced emptying rate observed with BP is associated with major changes in intragastric distribution of the meal absent with WB and S diets.