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Oxytocin, the sweet hormone?

Gareth Leng and Nancy Sabatiertrends in Endo and Met

Trends in Endocrinology and Metabolism (in press)

Mammalian neurons that produce oxytocin and vasopressin apparently evolved from an ancient cell type with both sensory and neurosecretory properties that probably linked reproductive functions to energy status and feeding behavior. Oxytocin in modern mammals is an autocrine/paracrine regulator of cell function, a systemic hormone, a neuromodulator released from neuronal axon terminals within the brain, and a “neurohormone”, acting within the brain at receptors distant from its site of release. Oxytocin is involved peripherally in electrolyte homeostasis, gastric motility, glucose homeostasis, adipogenesis and osteogenesis, and centrally in food reward, food choice and satiety. Oxytocin preferentially suppresses intake of sweet-tasting carbohydrates while improving glucose tolerance and supporting bone remodelling, making it an enticing translational target.

Ghrelin changes food preference from high fat diet to chow in schedule-fed rats

Tina Bake, Kim T.Hellgren, Suzanne L. Dickson

Presented at the European Obesity Summit, June 2016

Ghrelin is a gut peptide released from the empty stomach that increases food intake. It has also been linked to food-related behaviours such as food motivation, food reward and food anticipatory activity. Ghrelin levels in the blood are linked to meal pattern, increasing prior to feeding. To mimic human meal eating behaviour in animals we used a scheduled feeding (SF) paradigm in which rodents have ad libitum access to chow and in addition 2h access to highly palatable high fat diet (HFD). Previous studies with this paradigm have shown that both rats and mice will rapidly adapt their feeding behaviour and as a result binge-eat on HFD.

Here we sought to investigate the role of ghrelin during binge-like meal eating induced by SF. We utilised a combination of two different animal models: pharmacologically manipulated rats via acute administration of ghrelin or genetically modified mice lacking the growth hormone secretagogue receptor 1A (GHS-R1A). For acute injections of either ghrelin or vehicle into the lateral ventricle (ICV) or intra-VTA, rats were surgically implanted with guide cannulas and then habituated to SF for at least 2 weeks prior to injections. GHS-R1A-KO mice and their wildtype (WT) littermates were scheduled-fed for 4 weeks.

Remarkably and unexpectedly, we found that acutely injecting ghrelin ICV or intra-VTA resulted in a shift in food preference from high fat diet towards chow during the SF period without altering total daily energy consumption. However an increase of body weight was observed after ICV ghrelin. A fasting challenge also led to an increase in chow intake during the SF session but HFD intake did not reduce at the same time. GHS-R1A-KO mice were able to adapt and maintain large meals of HFD in a similar fashion as WT mice suggesting that the ghrelin signalling system may not have a critical role in 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 the food preference towards a healthier choice (from HFD to chow), effects that were clearly divergent from fasting.

Supported by EC (Nudge-it, 607310).


Parental beliefs about portion size, not children’s own beliefs, predict adiposity in children

C Potter, D Ferriday, RL Griggs, JP Hamilton-Shield, PJ Rogers, JM Brunstrom

Presented at the Society for the Study of Ingestive Behaviour meeting, July 2016

Recent increases in portion size are thought to play a causal role in promoting obesity in children. However, the underlying process remains unclear. We explored whether a child’s adiposity is predicted by parental beliefs about their child’s preferred portion size and/or by the child’s own beliefs. Overweight and lean children (N=217) were recruited from a randomised controlled trial (n=69) and a local science centre (n=148). For a range of main meals, parents provided estimates of their child’s ‘ideal’ and ‘maximum tolerated’ portion size. Children also completed the same tasks. Parents also reported their own preferred portion. Independent of a parent’s own preferred portion size and weight status, if a parent believed that their child preferred larger portion sizes (β=.34, p< .001) or could tolerate more food (β=.30, p< .001), then their child was more likely to be obese. However, children’s self-reported ideal (β=.024, p=.718) and maximum portions (β=-.085, p=.214) did not predict their own adiposity. The discrepancy between portions selected by children and those estimated by parents was greater in children who were lean. This suggests that when a parent underestimates their child’s preferred portion size then their child is less likely to be overweight. Given that meals tend to be served to children (they rarely self-select their own portions) this association merits serious consideration. 

Supported By: This research was supported by a 'stand-alone' LINK grant from the BBSRC(reference: BB/J005622/1) as well as the EU Seventh Framework Programme (FP7/2007-2013) under Grant Agreement 607310 (Nudge-it).

Effects of portion size on food choice

JM Brunstrom, A Jarvstad, RL Griggs, CM Potter, NR Evans, AA Martin, JCW Brooks,and  PJ Rogers

Presented at the Society for the Study of Ingestive Behaviour meeting, July 2016

Larger portions promote larger meals. However, the effect of portion size on food choice remains largely unexplored. In two studies we ‘deconstruct’ food choice to quantify the independent role of portion size, liking, and expected satiety. Participants (N= 24) ranked familiar lunch-time meals (N= 5) in order of preference. Separate ranks were obtained for equicaloric portions in the range 100 kcal to 800 kcal (100 kcal steps). In a second study participants (N= 24) evaluated a broader range of foods (N =9) in three different contexts, believing a) that the next meal would be at 7pm, b) that they would receive only a bite, and c) that they would be offered an additional course of their choosing immediately afterwards. When small portions were compared then expected satiety was a reliable and positive predictor of choice, playing a role equal to that of palatability. With larger portions, choice was motivated solely by palatability - expected satiety was a poor or even a negative predictor. In scenarios b and c (Study 2) any influence of expected satiety was eliminated. For the first time this work demonstrates that large portions change our strategy in food choice – orienting us toward foods that are palatable, including those that are energy dense. With smaller portions, choice is motivated by a ‘defence of meal pattern’ – a concern to prevent the return of a desire to eat between planned meals. 

Supported By: European Union Seventh Framework Programme (FP7/2007–2013 under Grant Agreement 607310 [Nudge-it])

“What time is my next meal?” Impulsive individuals choose smaller portions under conditions of uncertainty

Annie R. Zimmerman, Danielle Ferriday, Sarah R. Davies, Ashley A. Martin, Peter J. Rogers, and Jeffrey M. Brunstrom

Presented at the Society for the Study of Ingestive Behaviour meeting, July 2016

Both impulsivity and unstructured meal timings have been identified as risk factors for obesity. However, impulsivity is typically considered in relation to long-term health concerns. This is the first study to investigate impulsivity in tasks that require short-term thinking about meal timings. Information regarding inter-meal interval (IMI) allows meal planning. We sought to assess how uncertainty about IMIs influences portion decisions and whether impulsive individuals respond differently to the predictability of an IMI. In addition, we explored relationships between BMI, portion selection and impulsivity.
Participants (N= 90) selected portion sizes for lunch. In different trials, they were told to expect dinner at 17:00h, 21:00h or either 17:00h or 21:00h (uncertain IMI). They then completed a delay discounting task.

Participants chose larger portions when the IMI was longer (95% CI = .500 to .779 p =.00). There was a small but non-significant association between impulsivity and portion selection when the IMI was certain (95% CI = -.061 to .429, p = .15). In the uncertain condition, impulsive participants chose smaller portions (95% CI = .060 to .489, p =.02). Similarly, BMIs was associated with smaller portion selection in the uncertain condition (95% CI = -.506 to -.001, p =.03). Furthermore, impulsivity mediated a relationship between BMI and smaller portion selection in uncertainty (95% CI = -671.203 to -600.267, p = .02).

This is the first study to report an association between impulsivity, BMI and uncertain IMIs. We reason that impulsive individuals discounted concerns about potential ‘hunger’ between meals and selected smaller portions accordingly. Impulsivity mediated a relationship between BMI and smaller portions selected in uncertainty. Hence, impulsivity may be more likely to be expressed in a ‘chaotic’ eating environment. Theoretically, these findings are important because they illustrate how short-term discounting of meal times can influence portion-size decisions.

Via which neurons does leptin affect food reward?

R.A. Adan, R. Zessen, V. De Vrindt, A. Omrani, and G. Van der Plasse

Presented at the Society for the Study of Ingestive Behaviour meeting, July 2016

Leptin suppresses food restriction induced activity of midbrain dopamine neurons invivo, as well as the motivation to work for food reward. Although both the ventral tegmental area (VTA) as well as lateral hypothalamic (LH) neurons have been implicated in food seeking, the neuronal circuitry that mediates leptin-induced action on motivated food-seeking remains unknown. We here addressed which leptin sensitive neurons affect motivation for food reward. We find that increasing activity of dopamine neurons projecting to the nucleus accumbens increased the motivation to work for a food reward . In contrast, reducing cue-induced VTA dopamine neuronal firing (through optogenetic inhibition during reward consumption) decreased licking rates to obtain a sucrose reward. As such, these data clearly implicate the DA system in food-seeking behavior. We next investigated how leptin affects this behavior. Using slice electrophysiology in leptin receptor cre mice we characterized the connectivity and leptin sensitivity of VTA neurons. Finally, we used a chemogenetic approach to assess the function of leptin receptor expressing neurons in the LH and VTA during feeding and motivated food-seeking. Our data support the involvement of the LH in mediating the effects of leptin on motivation for food reward.

Supported By: EU projects NeuroFast, NudgeIT and Full4Health

Centrally Administered Ghrelin Acutely Influences Food Choice in Rodents

T Bake, E Schele, C Rabasa, and SL Dickson

Presented at the Society for the Study of Ingestive Behaviour meeting, July 2016

We sought to determine whether the orexigenic hormone, ghrelin, is involved in the intrinsic regulation of food choice in rodents. In rats offered a choice of palatable foods (sucrose pellets and lard) superimposed on regular chow for 2 weeks, that had high baseline lard intake, acute central delivery of ghrelin (ICV or intra-VTA) increased their chow intake over 3-fold, relative to vehicle-injected controls, measured at both 3 hr and 6 hr after injection. We also explored food choice after an overnight fast, when endogenous ghrelin levels are elevated, and found similar effects of dietary choice to those described for ghrelin. These effects of fasting on food choice were suppressed in models of suppressed ghrelin signaling (i.e. peripheral injection of a ghrelin receptor antagonist to rats and ghrelin receptor (GHSR) knock-out mice), implicating a role for endogenous ghrelin in the changes in food choice that occur after an overnight fast. Interestingly, rats on a palatable feeding schedule (high fat diet for 2 hrs each day with ad libitum access to chow), that develop binge-like behaviour for the high fat diet, also start to eat chow during the binge period under the influence of ghrelin.  Thus, in line with its role as a gut-brain hunger hormone, ghrelin appears to be able to acutely alter food choice, with notable effects to promote "healthy" chow intake, both in rats with high baseline fat intake, and in rats expressing binge-like feeding behaviour, and identify the VTA as a likely contributing neurobiological substrate for these effects.

Supported By: EC Project Nudge-it and Vetenskapsrådet

The influence of insulin on the prefrontal circuitry and food decisions

S Kullmann M Heni, M Hege, R Veit, HU Häring, A Fritsche, and H Preissl

Presented at the Society for the Study of Ingestive Behaviour meeting,  July 2016

The prefrontal cortex plays a crucial role for food decisions in an obesogenic environment, as it is of utmost importance in inhibitory control of eating behavior and reward-based decision-making. In our recent neuroimaging studies, we were able to show that the prefrontal cortex is particularly sensitive to increasing peripheral and central insulin levels. However, obese individuals more susceptible to disinhibited eating along with food craving show insulin resistance in the prefrontal cortex. Hence, insulin resistance of the prefrontal cortex may promote reduced inhibitory control towards food cues. Furthermore, increased prefrontal cortex activity to food cues is observed in successful dieters and in healthy volunteers when considering health consequences during pre-meal planning. Hence, increasing prefrontal functions and connections could be a possible mechanism to make healthy choices. We will discuss recent findings on food decision processes using functional magnetic resonance imaging and address the multiple effects of insulin action in the brain influencing food decisions. Furthermore, we address the possibility of enhancing prefrontal cortex activity and functional connectivity, by means of intranasal insulin and by modulating the individuals’ mind-set during pre-meal planning.

Neuronal correlates of pre-meal planning

MA Hege, R Veit, JM Brunstrom, PJ Rogers, A Fritsche, and H Preissl

Presented at the Society for the Study of Ingestive Behaviour meeting, July 2016

Meal sizes are not only controlled by physiological processes that generate fullness towards the end of a meal, but also by decisions about portion sizes before a meal begins. People can estimate the ‘expected satiety’ of different foods, which might even be a more important determinant of meal size than palatability. However, little is known about the integration of these factors during pre-meal planning and the neural correlates involved in these decisions. Thus, we designed an fMRI study in which healthy subjects (9f/9m, BMI: 19-24 kg/m², age: 18-31 y) were presented with visual stimuli of different meals with varying portion sizes. Subjects had to select their ideal portion size for lunch under different mindsets which addressed factors like expected satiety, palatability and self-control. Our results showed that these mindsets introduced behavioral changes in meal size selection and that these changes were gender specific. The final selection of a portion size was associated with increased activity in areas involved in decision making. When subjects had to consider health consequences, they showed increased activity in left prefrontal cortex and when they considered palatability, an increase in left orbitofrontal cortex was observed. These data indicate that different mindsets are associated with specific neuronal processes and the behavioral data suggest a gender specific effect in pre-meal planning.

Supported By: European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreement 607310 (Nudge-it)

Intranasal insulin enhances the functional connectivity of the brain and reduced subjective feeling of hunger

S Kullmann, M Heni,2,3, R Veit, HU Häring, A Fritsche and  H Preissl

Presented at the Society for the Study of Ingestive Behaviour meeting July 2016

Enhancing brain insulin action has beneficial effects on eating behavior and cognition. Studies in dementia suggest that intranasal insulin can enhance functional connectivity (FC) within the default-mode-network to improve cognition. Little is known, however, if intranasal insulin can influence brain FC in young healthy individuals to influence human eating behavior. Therefore, we performed functional magnetic resonance imaging in 47 healthy lean and obese participants (BMI range 19.5-39.3 kg/m2; age range 21-36 years) to measure resting-state FC of the brain before and 30 min after intranasal insulin or placebo application. We identified a significant increase in FC between the hippocampus and the prefrontal regions of the default-mode-network after intranasal insulin compared to placebo in lean and obese participants. Moreover, this enhanced FC correlated with the change in hunger after intranasal insulin application. Hence, participants with a stronger increase in FC revealed a decline in hunger 120 min after intranasal insulin. No such relationship was observed after placebo administration. Taken together, we were able to show that intranasal insulin enhances functional connections in the brain possibly explaining the beneficial effects of brain insulin action on metabolism.

Supported By: The study was supported in part by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.), by the Helmholtz Alliance ICEMED - I
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