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Intranasal insulin enhances brain functional connectivity mediating the relationship between adiposity and subjective feeling of hunger

Stephanie Kullmann, Martin Heni, Ralf Veit, Klaus Scheffler, Jürgen Machann, Hans-Ulrich Häring, Andreas Fritsche
& Hubert Preissl

Scientific Reports, (2017) 7 no 1627

Brain insulin sensitivity is an important link between metabolism and cognitive dysfunction. Intranasal insulin is a promising tool to investigate central insulin action in humans. We evaluated the acute effects of 160 U intranasal insulin on resting-state brain functional connectivity in healthy young adults. Twenty-five lean and twenty-two overweight and obese participants underwent functional magnetic resonance imaging, on two separate days, before and after intranasal insulin or placebo application. Insulin compared to placebo administration resulted in increased functional connectivity between the prefrontal regions of the default-mode network and the hippocampus as well as the hypothalamus. The change in hippocampal functional connectivity significantly correlated with visceral adipose tissue and the change in subjective feeling of hunger after intranasal insulin. Mediation analysis revealed that the intranasal insulin induced hippocampal functional connectivity increase served as a mediator, suppressing the relationship between visceral adipose tissue and hunger. The insulin-induced hypothalamic functional connectivity change showed a significant interaction with peripheral insulin sensitivity. Only participants with high peripheral insulin sensitivity showed a boost in hypothalamic functional connectivity. Hence, brain insulin action may regulate eating behavior and facilitate weight loss by modifying brain functional connectivity within and between cognitive and homeostatic brain

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High-sugar, but not high-fat, food activates supraoptic oxytocin neurones in the male rat

Catherine Hume, Nancy Sabatier and John Menzies

Endocrinology (in press)

Oxytocin is a potent anorexigen and is believed to have a role in satiety signalling. We developed rat models to study the activity of oxytocin neurones in response to voluntary consumption or oral gavage of foods using c-Fos immunohistochemistry and in vivo electrophysiology.

Using c-Fos expression as an indirect marker of neural activation, we showed that the percentage of magnocellular oxytocin neurones expressing c-Fos increased with voluntary consumption of sweetened condensed milk (SCM). To model the effect of food in the stomach, we gavaged anaesthetised rats with SCM. The percentage of supraoptic nucleus and paraventricular nucleus magnocellular oxytocin-immunoreactive neurones expressing c-Fos increased with SCM gavage but not with gastric distention. To further examine the activity of the supraoptic nucleus, we made in vivo electrophysiological recordings from SON neurones while anaesthetised rats were gavaged with SCM or single cream. Pharmacologically identified oxytocin neurones responded to SCM gavage with a linear, proportional and sustained increase in firing rate but cream gavage resulted in a transient reduction in firing rate. Blood glucose increased after SCM gavage but not cream gavage. Plasma osmolarity and plasma sodium were unchanged throughout.

We show that in response to a high-sugar, but not high-fat, food in the stomach, there is an increase in the activity of oxytocin neurones. This does not appear to be a consequence of stomach distention or changes in osmotic pressure. Our data suggest that the presence of specific foods with different macronutrient profiles in the stomach differentially regulates the activity of oxytocin neurones.

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Keeping Pace with Your Eating: Visual Feedback Affects Eating Rate in Humans

Laura L. Wilkinson, Danielle Ferriday, Matthew L. Bosworth , Nicolas Godinot ,Nathalie Martin, Peter J. Rogers, Jeffrey M. Brunstrom

Plos one FEb 2016 1-13

Deliberately eating at a slower pace promotes satiation and eating quickly has been associated with a higher body mass index. Therefore, understanding factors that affect eating rate should be given high priority. Eating rate is affected by the physical/textural properties of a food, by motivational state, and by portion size and palatability. This study explored the prospect that eating rate is also influenced by a hitherto unexplored cognitive process that uses ongoing perceptual estimates of the volume of food remaining in a container to adjust intake during a meal. A 2 (amount seen; 300ml or 500ml) x 2 (amount eaten; 300ml or 500ml) between-subjects design was employed (10 participants in each condition). In two ‘congruent’ conditions, the same amount was seen at the outset and then subsequently consumed (300ml or 500ml). To dissociate visual feedback of portion size and actual amount consumed, food was covertly added or removed from a bowl using a peristaltic pump. This created two additional ‘incongruent’ conditions, in which 300ml was seen but 500ml was eaten or vice versa.We repeated these conditions using a savoury soup and a sweet dessert. Eating rate (ml per second) was assessed during lunch. After lunch we assessed fullness over a 60-minute period. In the congruent conditions, eating rate was unaffected by the actual volume of food that was consumed (300ml or 500ml). By contrast, we observed a marked difference across the incongruent conditions. Specifically, participants who saw 300ml but actually consumed 500ml ate at a faster rate than participants
who saw 500ml but actually consumed 300ml. Participants were unaware that their portion size had been manipulated. Nevertheless, when it disappeared faster or slower than anticipated they adjusted their rate of eating accordingly. This suggests that the control of eating rate involves visual feedback and is not a simple reflexive response to orosensory stimulation.

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Computerized measurement of anticipated anxiety from eating increasing portions of food in adolescents with and without anorexia nervosa: Pilot studies

H.R. Kissileff , J.M. Brunstrom , R. Tesser, D. Bellace, S. Berthod , J.C. Thornton, K. Halmi.

Appetite 97 (2016) 160-168

Dieting and excessive fear of eating coexist in vulnerable individuals, which may progress to anorexia nervosa [AN], but there is no objective measure of this fear. Therefore, we adapted a computer  program that was previously developed to measure the satiating effects of foods in order to explore the potential of food to induce anxiety and fear of eating in adolescent girls. Twenty four adolescents (AN) and ten healthy controls without eating disorders rated pictures of different  types of foods in varying sized portions as too large or too small and rated the expected anxiety
of five different portions (20e320 kcal). Two low energy dense (potatoes and rice) and two high  energy dense (pizza and M&Ms) foods were used. The regression coefficient of line lengths (0e100 mm)  marked from “No anxiety” to ”this would give me a panic attack”, regressed from portions shown, was  the measure of “expected anxiety” for a given food. The maximum tolerated portion size [kcal]  (MTPS),  computed by method of constant stimulus from portions shown, was significantly smaller for  high energy dense foods, whereas the ex- pected anxiety response was greater, for all foods, for  patients compared to controls. For both groups, expected anxiety responses were steeper, and
maximum tolerated portion sizes were larger, for low, than high, energy dense foods. Both maximum  tolerated portion size and expected anxiety response were significantly predicted by severity of  illness for the patients. Those who had larger maximum tolerated portion sizes had smaller  anticipated anxiety to increasing portion sizes. Visual size had a greater in- fluence than energy  content for these responses. This method could be used to quantify the anxiety inducing potential  of foods and for studies with neuro-imaging and phenotypic clarifications.

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Homeostatic Responses to Palatable Food Consumption in Satiated Rats

Catherine Hume, Barbara Jachs, and John Menzies

Obesity (2016) 24, 2126-2132.

Energy intake is regulated by overlapping homeostatic and hedonic systems. Consumption
of palatable foods has been implicated in weight gain, but this assumes that homeostatic control  systems do not accurately detect this hedonically driven energy intake. This study tested this  assumption, hypothesizing that satiated rats would reduce their voluntary food intake and maintain  a stable body weight after consuming a palatable food.
Lean rats or rats previously exposed to an obesogenic diet were schedule-fed with fixed or  varying amounts of palatable sweetened condensed milk (SCM) daily, and their voluntary energy  intake and body weight were monitored. During scheduled feeding of SCM, rats voluntarily reduced bland food consumption and main-  tained a stable body weight. This behavior was also seen in rats with access to an obesogenic diet  and was independent of the predictability of SCM access. However, lean rats offered large amounts  of SCM showed an increase in total energy intake. To test whether a nutrient deficiency drove this under-compensatory behavior, SCM was enriched with protein. However, no effect was seen on  voluntary energy intake. In schedule-fed rats, compensatory reductions in voluntary energy intake were seen,  but under-compensation was observed if large amounts of SCM were consumed.

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Electro/magnetoencephalographic signatures of human brain insulin resistance

Maike A Hege, Stephanie Kullmann, Martin Heni, Franziska Schleger, Katarzyna Linder, Andreas Fritsche  and Hubert Preissl

Current opinion in Behavioural Sciences Vol 9, 163-168

Human insulin action influences eating behavior, peripheral metabolism and cognition. Detailed insights into the neuronal processes related to human brain insulin action can be obtained by direct measures of neuronal activity with
electroencephalography and magnetoencephalography.
Results of recent studies show that spontaneous, task and stimulus related neuronal activity is modulated by insulin and that several factors like increased body weight and body composition can result in brain insulin resistance. Recent technological advances even allow the investigation of human brain functions in utero in relation to the metabolic status of the mother and indicate an effect of the mother’s insulin sensitivity on the brain function of the fetus. In conclusion, studies based on direct neuronal measurements may help to determine the developmental trajectory related to insulin action and resistance.

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A novel approach to map induced activation of neuronal networks using chemogenetics and functional neuroimaging in rats: A proof-of-concept study on the mesocorticolimbic system

Theresia J.M. Roelofs, Jeroen P.H. Verharen, Geralda A.F. van Tilborg ,Linde Boekhoudt ,Annette van der Toorn, Johannes W. de Jong ,Mieneke C.M. Luijendijk ,Willem M. Otte,Roger A.H. Adan  

Neuroimage 156 (2017) 109-118

Linking neural circuit activation at whole-brain level to neuronal activity at cellular level remains one of the major challenges in neuroscience research. We set up a novel functional neuroimaging approach to map global effects of locally induced activation of specific midbrain projection neurons using chemogenetics (Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-technology) combined with pharmacological magnetic resonance imaging (phMRI) in the rat mesocorticolimbic system. Chemogenetic activation of DREADD-targeted mesolimbic or mesocortical pathways, i.e. projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) or medial prefrontal cortex (mPFC), respectively, induced significant blood oxygenation level-dependent (BOLD) responses in areas with DREADD expression, but also in remote defined neural circuitry without DREADD expression. The time-course of brain activation corresponded with the behavioral output measure, i.e. locomotor (hyper)activity, in the mesolimbic pathway-targeted group. Chemogenetic activation specifically increased neuronal activity, whereas functional connectivity assessed with resting state functional MRI (rs-fMRI) remained stable. Positive and negative BOLD responses distinctively reflected simultaneous ventral pallidum activation and substantia nigra pars reticulata deactivation, respectively, demonstrating the concept of mesocorticolimbic network activity with concurrent activation of the direct and indirect pathways following stimulation of specific midbrain projection neurons. The presented methodology provides straightforward and widely applicable opportunities to elucidate relationships between local neuronal activity and global network activity in a controllable manner, which will increase our understanding of the functioning and dysfunctioning of large-scale neuronal networks in health and disease.


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A tale of gastric layering and sieving: Gastric emptying of a liquid meal with water blended in or consumed separately

Guido Camps, Monica Marsa, Cees de Graaf, Paul A.M. Smeets

Physiology & Behaviour (in press)

The process of gastric emptying determines how fast gastric content is delivered to the small intestine. It has been shown that solids empty slower than liquids and that a blended soup empties slower than the same soup as broth and chunks, due to the liquid fraction emptying more quickly. This process of ‘gastric sieving’ has not been investigated for liquid foods.
To determine whether gastric sieving of water can also occur for liquid foods. Two groups of men participated in a parallel design (n =15, age 22.6 ± 2.4 y, BMI 22.6 ± 1.8 kg/ m2, and n =19, age 22.2 ± 2.5 y, BMI 21.8 ± 1.5 kg/m2) and consumed an isocaloric shake (2093 kJ, CARBOHYDRATES: 71 g, FAT: 18 g, PROTEIN: 34 g), either in a 500-mL version (MIXED) or as a 150-mL shake followed by 350 mL water (SEPARATE). Participants provided appetite ratings and were scanned using MRI to determine gastric emptying rate and volume at three time-points within 35 min post ingestion.
Gastric emptying - the percentage emptied in 35 min was significantly smaller for MIXED (29 ± 19%) than for SEPARATE (57 ± 11%, p < 0.001).  In the present study we show that gastric sieving can occur for liquid foods; water is able to drain
from the stomach while a layer of nutrient rich liquid is retained. In indirect gastric emptying measurements, the
behavior of labelling agents may be affected by the layering and confound emptying measurements

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Modulation of attentional networks by food-related disinhibition

Maike A. Hege , Krunoslav T. Stingl, Ralf Veit, and Hubert Preissl

Physiology and Behaviour 2017 (in press)

The risk of weight gain is especially related to disinhibition, which indicates the responsiveness to external food stimuli with associated disruptions in eating control.We adapted a food-related version of the attention network task and used functional magnetic resonance imaging to study the effects of disinhibition on attentional networks in 19 normal-weight participants. High disinhibition scores were associated with a rapid reorienting response to food pictures after invalid cueing and with an enhanced alerting effect of awarning cue signalizing the upcoming appearance of a food picture. Imaging data revealed activation of a right-lateralized ventral attention network during reorienting. The faster the reorienting and the higher the disinhibition score, the less activation of this network was observed. The alerting contrast showed activation in visual, temporo-parietal and anterior sites. These modulations of attentional networks by food-related disinhibition might be related to an attentional bias to energy dense and palatable food and increased intake of food in disinhibited individuals.

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Acute ghrelin changes food preference from high fat diet to chow during binge-like eating in rodents

Tina Bake, Kim T Hellgren and Suzanne L Dickson

Journal of Neuroendocrinology 2017, Vol 29 1-12

Ghrelin, an orexigenic hormone released from the empty stomach, provides a gut–brain signal that promotes many appetitive behaviours, including anticipatory and goal-directed behaviours for palatable treats high in sugar and/or fat. In the present study, we aimed to determine whether ghrelin is able to influence and/or may even have a role in binge-like eating behaviour in rodents. Accordingly, we used a palatable scheduled feeding (PSF) paradigm in which ad lib. chow-fed rodents are trained to ‘binge’ on a high-fat diet (HFD) offered each day for a limited period of 2 hours. After 2 weeks of habituation to this paradigm, on the test day and immediately prior to the 2-hour PSF,rats were administered ghrelin or vehicle solution by the i.c.v. route. Remarkably and unexpectedly, during the palatable scheduled feed, when rats normally only binge on the HFD, those injected with i.c.v. ghrelin started to eat more chow and chow intake remained above baseline for the rest of the 24-hour day. We identify the ventral tegmental
area (VTA) (a key brain area involved in food reward) as a substrate involved because these effects could be reproduced, in part, by intra-VTA delivery of ghrelin.
Fasting, which increases endogenous ghrelin, immediately prior to a palatable schedule feed also increased chow intake during/after the schedule feed but, in contrast to ghrelin injection, did not reduce HFD intake. Chronic continuous central ghrelin infusion over several weeks enhanced binge-like behaviour in palatable schedule fed rats.
Over a 4-week period, GHS‐R1A‐KO mice were able to adapt and maintain large meals of HFD in a manner similar to wild-type mice, suggesting that ghrelin signalling may not have a critical role in the acquisition or maintenance in this kind of feeding behaviour. In conclusion, ghrelin appears to act as a modulating factor for binge‐like eating behaviour
by shifting food preference towards a more nutritious choice (from HFD to chow), with these effects being somewhat divergent from fasting.

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