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Genetic predisposition to obesity affects behavioural traits includingfood reward and anxiety-like behaviour in rats

Heike Vogel, Maria Kraemer, Cristina Rabasa, Kaisa Askevik, Roger A.H. Adan,Suzanne L. Dickson

Behavioural Brain Research, 328 (2017) 95-104

tHere we sought to define behavioural traits linked to anxiety, reward, and exploration in different strainsof rats commonly used in obesity research. We hypothesized that genetic variance may contributenot only to their metabolic phenotype (that is well documented) but also to the expression of thesebehavioural traits. Rat strains that differ in their susceptibility to develop an obese phenotype (Sprague-Dawley, Obese Prone, Obese Resistant, and Zucker rats) were exposed to a number of behavioural testsstarting at the age of 8 weeks. We found a similar phenotype in the obesity susceptible models, ObeseProne and Zucker rats, with a lower locomotor activity, exploratory activity, and higher level of anxiety-like behaviour in comparison to the leaner Obese Resistant strain. We did not find evidence that rat strainswith a genetic predisposition to obesity differed in their ability to experience reward from chocolate (ina condition place preference task). However, Zucker rats show higher motivated behaviour for sucrosecompared to Obese Resistant rats when the effort required to obtain palatable food is relatively low.Together our data demonstrate that rat strains that differ in their genetic predisposition to developobesity also differ in their performance in behavioural tests linked to anxiety, exploration, and rewardand that these differences are independent of body weight. We conclude that genetic variations whichdetermine body weight and the aforementioned behaviours co-exist but that future studies are requiredto identify whether (and which) common genes are involved.

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The determinants of food choice

Gareth Leng, Roger A. H. Adan, Michele Belot, Jeffrey M. Brunstrom, Kees de Graaf, Suzanne L. Dickson, Todd Hare, Silvia Maier, John Menzies, Hubert Preissl, Lucia A. Reisch, Peter J. Rogers and Paul A. M. Smeets

in "Proceedings of the Nutrition Society"  76, 316-327,  Summer Meeting University College Dublin July 2016

Conference on ‘New technology in nutrition research and practice’

Health nudge interventions to steer people into healthier lifestyles are increasingly applied by governments worldwide, and it is natural to look to such approaches to improve health by altering what people choose to eat. However, to produce policy recommendations that are likely to be effective, we need to be able to make valid predictions about the consequences of proposed interventions, and for this, we need a better understanding of the determinants of food choice. These determinants include dietary components (e.g. highly palatable foods and alcohol), but also diverse cultural and social pressures, cognitive-affective factors (perceived stress, health attitude, anxiety and depression), and familial, genetic and epigenetic influences on personality characteristics. In addition, our choices are influenced by an array of physiological mechanisms, including signals to the brain from the gastrointestinal tract and adipose tissue, which affect not only our hunger and satiety but also our motivation to eat particular nutrients, and the reward we experience from eating. Thus, to develop the evidence base necessary for effective policies, we need to build bridges across different levels of knowledge and understanding. This requires experimental models that can fill in the gaps in our understanding that are needed to inform policy, translational models that connect mechanistic understanding from laboratory studies to the real life human condition, and formal models that encapsulate scientific knowledge from diverse disciplines, and which embed understanding in a way that enables policy-relevant predictions to be made. Here we review recent developments in these areas.

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Spike patterning in oxytocin neurons: Capturing physiological behaviour with Hodgkin-Huxley and integrate-and-fire models

Gareth Leng, Trystan Leng, Duncan J MacGregor

PlosONE, 12 (7) 2107

Integrate-and-fire (IF) models can provide close matches to the discharge activity of neurons, but do they oversimplify the biophysical properties of the neurons? A single compartment Hodgkin-Huxley (HH) model of the oxytocin neuron has previously been developed, incorporating biophysical measurements of channel properties obtained in vitro. A simpler modified integrate-and-fire model has also been developed, which can match well the characteristic spike patterning of oxytocin neurons as observed in vivo. Here, we extended the HH model to incorporate synaptic input, to enable us to compare spike activity in the model with experimental data obtained in vivo. We refined the HH model parameters to closely match the data, and then matched the same experimental data with a modified IF model, using an evolutionary algorithm to optimise parameter matching. Finally we compared the properties of the modified HH model with those of the IF model to seek an explanation for differences between spike patterning in vitro and in vivo. We show that, with slight modifications, the original HH model, like the IF model, is able to closely match both the interspike interval (ISI) distributions of oxytocin neurons and the observed variability of spike firing rates in vivo and in vitro. This close match of both models to data depends on the presence of a slow activity-dependent hyperpolarisation (AHP); this is represented in both models and the parameters used in the HH model representation match well with optimal parameters of the IF model found by an evolutionary algorithm. The ability of both models to fit data closely also depends on a shorter hyperpolarising after potential (HAP); this is explicitly represented in the IF model, but in the HH model, it emerges from a combination of several components. The critical elements of this combination are identified.

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Individual variability in preference for energy-dense foods fails to predict child BMI percentile

Christina Potter, Rebecca L. Griggs, Danielle Ferriday, Peter J. Rogers, Jeffrey M. Brunstrom

Physiology & Behaviour 176 (2017) 3-8

Many studies show that higher dietary energy density is associated with greater body weight. Here we explored two propositions: i) that child BMI percentile is associated with individual differences in children's relative preference for energy-dense foods, ii) that child BMI percentile is associated with the same individual differences between their parents. Child-parent dyads were recruited from a local interactive science center in Bristol (UK). Using computerized tasks, participants ranked their preference and rated their liking for a range of snack foods that varied in energy density. Children (aged 3–14 years, N=110) and parents completed the tasks for themselves. Parents also completed two further tasks in which they ranked the foods in the order that they would prioritize for their child, and again, in the order that they thought their child would choose. Children preferred (t(109) =3.91, p < 0.001) and better liked the taste of (t(109) =3.28, p=0.001) higher energy-dense foods, and parents correctly estimated this outcome (t(109) = 7.18, p < 0.001). Conversely, lower energy-dense foods were preferred (t(109) =−4.63, p < 0.001), better liked (t(109) =−2.75, p=0.007) and served (t(109) = −15.06, p < 0.001) by parents. However, we found no evidence that child BMI percentile was associated with child or parent preference for, or liking of, energy-dense foods. Therefore, we suggest that the observed
relationship between dietary energy density and body weight is not explained by individual differences in preference for energy density.

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Food portion size area mediates energy effects on expected anxiety in anorexia nervosa

Musya Herzog , Christopher R. Douglas , Harry R. Kissileff *, Jeffrey M. Brunstrom , Katherine Ann Halmi

Appetite 112 (2017) 17-22

A study in which adolescent patients with anorexia nervosa (n ¼ 24) rated their expected food-anxiety in response to images of portions of food (potatoes, rice pizza, and M&Ms) showed that lower energy-dense foods elicited higher expected anxiety per kilocalorie than higher energy-dense foods. However, the area of the portion sizes could be an unmeasured variable driving the anxiety response. To test the hypothesis that area mediates the effects of energy content on expected anxiety, the same images of portions were measured in area (cm2), and standardized values of expected anxiety were regressed from standardized values of energy and area of portions. With regression of expected anxiety from portion size in area, M&Ms, which had the highest energy density of the four foods, elicited the highest expected anxiety slope (b ¼ 1.75), which was significantly different from the expected anxiety slopes of the other three foods (b range ¼ 0.67 e 0.96). Area was confirmed as a mediator of energy effects from loss of significance of the slopes when area was added to the regression of expected anxiety from energy x food. When expected anxiety was regressed from food, area, energy and area by energy interaction, area accounted for 5.7 times more variance than energy, and b for area (0.7) was significantly larger (by 0.52, SE ¼ 0.15, t ¼ 3.4, p ¼ 0.0007) than b for energy (0.19). Area could be a learned cue for the energy content of food portions, and thus, for weight gain potential, which triggers anxiety in patients with anorexia nervosa


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Variation in the Oral Processing of Everyday Meals Is Associated with Fullness and Meal Size; A Potential Nudge to Reduce Energy Intake?

Danielle Ferriday , Matthew L. Bosworth, Nicolas Godinot, Nathalie Martin, Ciarán G. Forde, Emmy Van Den Heuvel, Sarah L. Appleton, Felix J. Mercer Moss, Peter J. Rogers and Jeffrey M. Brunstrom

Nutrients 2016 8 315

Laboratory studies have demonstrated that experimental manipulations of oral processing can have a marked effect on energy intake. Here, we explored whether variations in oral processing across a range of unmodified everyday meals could affect post-meal fullness and meal size. In Study 1, female participants (N = 12) attended the laboratory over 20 lunchtime sessions to consume a 400-kcal portion of a different commercially available pre-packaged meal. Prior to consumption, expected satiation was assessed. During eachmeal, oral processingwas characterised using: (i) video-recordings of the mouth and (ii) real-time measures of plate weight. Hunger and fullness ratings were elicited
pre- and post-consumption, and for a further three hours. Foods that were eaten slowly had higher expected satiation and delivered more satiation and satiety. Building on these findings, in Study 2 we selected two meals (identical energy density) from Study 1 that were equally liked but maximised differences in oral processing. On separate days, male and female participants (N = 24) consumed a 400-kcal portion of either the “fast” or “slow” meal followed by an ad libitum meal (either the same food or a dessert). When continuing with the same food, participants consumed less of the slow meal. Further, differences in food intake during the ad libitum meal were not compensated at a subsequent snacking opportunity an hour later. Together, these findings suggest that variations in oral processing across a range of unmodified everyday meals can affect fullness after consuming a fixed portion and can also impact meal size. Modifying food form to encourage increased oral processing (albeit to a lesser extent than in experimental manipulations) might represent a viable target for food manufacturers to help to nudge consumers to manage their weight.

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Higher Heart-Rate Variability Is Associated with Ventromedial Prefrontal Cortex Activity and Increased Resistance to Temptation in Dietary Self-Control Challenges

Silvia U. Maier and Todd A. Hare

Journal of Neuroscience Jan 11 2017 37(2) 446-455

Higher levels of self-control in decision making have been linked to better psychosocial and physical health. A similar link to health outcomes has been reported for heart-rate variability (HRV), a marker of physiological flexibility. Here, we sought to link these two, largely separate, research domains by testing the hypothesis that greater HRV would be associated with better dietary self-control in humans. Specifically, we examined whether total HRV at sedentary rest (measured as the SD of normal-to-normal intervals) can serve as a biomarker for the neurophysiological adaptability that putatively underlies self-controlled behavior. We found that HRV explained a significant portion of the individual variability in dietary self-control, with individuals having higher HRV being better able to downregulate their cravings in the face of taste temptations. Furthermore, HRV was associated with activity patterns in the ventromedial prefrontal cortex (vmPFC), a key node in the brain’s valuation and decision circuitry. Specifically, individuals with higher HRV showed both higher overall vmPFC blood-oxygen-level-dependent activity and attenuated taste representations when presented with a dietary self-control challenge. Last, the behavioral and neural associations withHRVwere consistent across both our stress induction and control experimental conditions. The stability of this association across experimental conditions suggests that HRV may serve as both a readily obtainable and robust biomarker for self-control ability across environmental contexts.

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Modulation of sweet preference by the actual and anticipated consequences of eating

Ashley A. Martin, Danielle Ferriday, Peter J. Rogers, Jeffrey M. Brunstrom

Appetite  107(2016) 575-584

Previous research has shown that non-human animals exhibit an inverted-U pattern of sweet preference,with consumption increasing across moderate levels of sweetness and then declining for high levels of sweetness. In rodents, this pattern reflects an avoidance of the postingestive effects of consuming energy-dense sugar solutions (conditioned satiation). Here, we examined whether humans also adjust their preferences to compensate for the anticipated energy content/satiating outcomes of consuming sweetened foods. In two experiments (each N ¼ 40), participants were asked to taste and imagine eating small (15 g) and large (250 g) portions of five novel desserts that varied in sweetness. Participants evaluated the desserts' expected satiety, expected satiation, and expected sickliness. A measure of estimated energy content was also derived using a computerized energy compensation test. This procedure was completed before and after consuming a standard lunch. Across both experiments, results
confirmed that participants preferred a less sweet dessert when asked to imagine eating a large versus a small portion, and when rating the dessert in a fed versus fasted state. We also obtained evidence that participants anticipated more energy from the sweeter desserts (even in Experiment 2 when half of the participants were informed that the desserts were equated for energy content). However we found only partial evidence for anticipated satiationdexpected sickliness was related systematically to increases in sweetness, but expected satiation and expected satiety were only weakly influenced. These findings raise questions about the role of sweetness in the control of food intake (in humans) and the degree to which ‘sweet-calorie learning’ occurs in complex dietary environments where sweetness may actually be a poor predictor of the energy content of foods.

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Connecting biology with psychology to make sense of appetite control

P. J. Rogers,D. Ferriday, S. A. Jebb and J. M. Brunstrom

Nutrition Bulletin, 41 344-352

Eating  more  than  is  required  to  maintain  bodyweight  is  weakly  resisted physiologically, as appetite does not closely track  body  energy  balance.  What does limit energy intake is the capacity of the gut to accommodate and process what is eaten. As the gut empties, we are ready to eat again. We typically refer to this absence of fullness as ‘hunger’, but in this state, even when it is prolonged (e.g. by missing one or two meals), our mental and physical performance is not compromised because body energy stores are mobilised to sustain energy supply to our brain and muscles. We illustrate this by discussing research on the effects of missing breakfast. Contrary to conventional wisdom, it appears that missing breakfast leads to a reduction in total daily energy intake and does not impair cognitive function (in adequately nourished
individuals). The problem with missing a meal or eating smaller meals, however, is that we miss out on (some of) the pleasure of eating (food reward). In current studies, we are investigating how to offset the reduced reward value of smaller food portions, by, for example, altering flavour intensity, food variety and unit size, in order to maintain overall meal satisfaction and thereby reduce or eliminate subsequent compensatory  eating.

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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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