Ghrelin is related to lower brain reward activation during touch

The gut hormone ghrelin drives food motivation and increases food intake, but it is also involved in the anticipation of and response to rewards other than food. This pre-registered study investigated how naturally varying ghrelin concentrations affect the processing of touch as a social reward in humans. Sixty-seven volunteers received slow caressing touch (so-called CT-targeted touch) as a social reward and control touch on their shins during 3T functional imaging on two test days. On one occasion, participants were fasted, and on another, they received a meal. On each occasion, plasma ghrelin was measured at three time points. All touch was rated as more pleasant after the meal, but there was no association between ghrelin concentrations and pleasantness. CT-targeted touch was rated as the most pleasant and activated somatosensory and reward networks (whole brain). A region-of-interest in the right medial orbitofrontal cortex (mOFC) showed lower activation during all touches, the higher the ghrelin concentrations were. During CT-targeted touch, a larger satiety response (ghrelin decrease after the meal) was associated with higher mOFC activation, and this mOFC activation was associated with higher experienced pleasantness. Overall, higher ghrelin concentrations appear to be related to a lower reward value for touch. Ghrelin may reduce the value of social stimuli, such as touch, to promote food search and intake in a state of low energy. This suggests that the role of ghrelin goes beyond assigning value to food reward.publishedVersio

Body fat regulating neuropeptides: relation to interleukines and gut microbiota

Previous studies have shown that mice lacking interleukin-6 (IL-6), an important cytokine in the immune system, develop obesity, and that central, but not peripheral, administration of IL-6 induces energy expenditure. These findings suggest that IL-6 suppresses fat mass through the central nervous system. The mechanism behind this, however, is not understood. The aim of this thesis was to investigate possible neurobiological mechanisms, by which IL-6, during health, could exert its fat suppressing effect. Using immunohistochemistry, we aimed to map the distribution of the IL-6 receptor α (IL-6Rα) in human and mouse hypothalamus. In IL-6 knockout mice, we measured the gene expression of key hypothalamic neuropeptides known to regulate energy homeostasis. In mice, IL-6Rα was present mainly on neurons, and was widely distributed throughout the hypothalamus. IL-6Rα was found in a large number of neurons in the fat suppressing arcuate nucleus (ARC) and paraventricular nucleus (PVN), as well as in the fat promoting lateral hypothalamic area (LHA). We also found the IL-6Rα to be co-localized with several energy balance regulating neuropeptides in these hypothalamic sites, for instance with orexin and melanin concentrating hormone (MCH) in the LHA. In humans, IL-6Rα was only found in MCH neurons, but virtually all MCH neurons contained IL-6Rα. Depletion of IL-6 reduced the expression of the fat suppressing neuropeptides corticotrophin-releasing hormone (CRH) and oxytocin, as well as of arginine-vasopressin (AVP). In addition, we found IL-6Rα on neurons that produce these neuropeptides. This indicates that IL-6 could directly act on these neurons to increase the expression of CRH, oxytocin and AVP. Depletion of IL-6 induced the expression of the fat suppressing cytokine IL-1. In addition, IL-6 expression was reduced in mice with IL-1 receptor 1 knockout. This indicates that, in the hypothalamus, IL-1 receptor 1 signaling increase IL-6 expression, while IL-6 decreases IL-1 expression. Based on our findings in this thesis we speculate that IL-6 could act on several hypothalamic neurons and sites involved in energy homeostasis to increase energy expenditure and eventually weight loss in mice, while a similar effect could by exerted via the pro-obesity neuropeptide MCH in humans. Previous studies show that gut microbiota contributes to obesity, in part by facilitating nutritional uptake, but probably also through other mechanisms. We aimed to investigate possible effects of gut microbiota on central energy balance regulation. We measured the gene expression of several important energy balance regulating neuropeptides in the hypothalamus and brainstem of germ free mice. The fat suppressing neuropeptides glucagon-like peptide-1(GLP-1) and brain-derived neurotrophic factor (BDNF) was downregulated in the presence of gut microbiota, which could explain the elevated fat mass. In addition, we found that mice with gut microbiota were less sensitive to leptin, providing another mechanism by which gut microbiota could increase fat mass. In conclution, our findings are in line the assumption that components of the immune system and the commensal gut microbiota can affect fat mass in part via energy balance-regulating circuits in the brain

Centrally Administered Ghrelin Acutely Influences Food Choice in Rodents.

We sought to determine whether the orexigenic hormone, ghrelin, is involved in the intrinsic regulation of food choice in rats. Ghrelin would seem suited to serve such a role given that it signals hunger information from the stomach to brain areas important for feeding control, including the hypothalamus and reward system (e.g. ventral tegmental area, VTA). Thus, in rats offered a choice of palatable foods (sucrose pellets and lard) superimposed on regular chow for 2 weeks, we explored whether acute central delivery of ghrelin (intracerebroventricular (ICV) or intra-VTA) is able to redirect their dietary choice. The major unexpected finding is that, in rats with high baseline lard intake, acute ICV ghrelin injection increased their chow intake over 3-fold, relative to vehicle-injected controls, measured at both 3 hr and 6 hr after injection. Similar effects were observed when ghrelin was delivered to the VTA, thereby identifying the VTA as a likely contributing neurobiological substrate for these effects. 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. 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, and identify the VTA as a likely contributing neurobiological substrate for these effects

Ghrelin Induces Place Preference for Social Interaction in the Larger Peer of a Male Rat Pair

Social interaction is important for survival in most social species including humans. To ensure social activities, individuals experience reward from social interaction, generating a powerfully reinforcing process. Here we hypothesized that reward from social interaction in a juvenile male rat pair may be enhanced by ghrelin, a circulating hormone that has been shown to enhance reward from other natural (e.g. food, sex) as well as artificial reinforcers (e.g. alcohol and other drugs of abuse). To this end, we assessed the impact of ghrelin and a ghrelin antagonist on preference for a chamber previously paired to the presence of a social partner in a conditioned place preference paradigm. We found that ghrelin increased and a ghrelin antagonist decreased preference for social interaction, but only in the heavier partner in a social pair. In addition, we found that administered ghrelin induced a positive association between preference for social interaction and body weight difference within socially interacting pairs, where larger ghrelin treated rats preferred social interaction, whereas smaller ghrelin treated rats avoided it, which raises the question if ghrelin could have a role in implementing social hierarchies in rats. In summary, we conclude that ghrelin signaling increases the reward from social interaction in a manner that reflects the degree of divergence in body weight between the social pair

Impact of ICV ghrelin on dietary choice.

<p>Impact of acute intracerebroventricular (ICV) injection of ghrelin on total energy intake and dietary choice during (A) 3 hr, (B) 6 hr and (C) 24 hr, in rats (n = 18) that had been <i>ad libitum</i> fed a choice diet comprising normal chow, 1 g sucrose pellets and lard (saturated animal fat) over the previous 14 days. All rats received ghrelin and vehicle solution in a cross over design with one day washout between injections. *P<0.05, **P<0.01, ***P<0.001.</p

Impact of ghrelin receptor knockout on dietary choice.

<p>Total energy intake and dietary choice were measured during (A) 3 hr, (B) 6 hr and (C) 24 hr after the end of an overnight fast, in ghrelin receptor knockout mice (GHSR-KO) and wild-type (WT) controls that had been <i>ad libitum</i> fed a choice diet comprising normal chow, 1 g sucrose pellets and lard (saturated animal fat) for 14 days prior to the overnight fast. **P<0.01 (one-way ANOVA).</p

Stability of daily food selection.

<p>Stability of daily (24 hr) food selection in rats (n = 18) offered an <i>ad libitum</i> free choice diet of normal chow, 1 g sucrose pellets and lard (a saturated animal fat). Data are shown for the last 4 baseline days (day 11–14) prior to ICV injection, and for the injection days in which 2 μg ghrelin or aCSF were administered. The data are expressed as mean ± SEM kcal consumed as % of daily total kcal intake.</p

Impact of fasting and peripherally administered ghrelin receptor antagonist on dietary choice.

<p>Impact of acute intraperitoneal injection of a ghrelin receptor antagonist on fasting-induced changes in total energy intake and dietary choice measured during (A) 3 hr, (B) 6 hr and (C) 24 hr after the end of an overnight fast, in rats (n = 24) that had been <i>ad libitum</i> fed a choice diet comprising normal chow, 1 g sucrose pellets and lard (saturated animal fat) for 14 days prior to fast. All rats received the antagonist and saline solution in a cross over design with one day washout between injections. In panels A and B; **P<0.01. In panel C, the letters indicate significant differences (rANOVA, P<0.01).</p

Impact of intra-VTA ghrelin on dietary choice.

<p>Impact of acute intra-VTA (ventral tegmental area) injection of ghrelin on total energy intake and dietary choice during (A) 3 hr, (B) 6 hr and (C) 24 hr, in rats (n = 17) that had been <i>ad libitum</i> fed a choice diet comprising normal chow, 1 g sucrose pellets and lard (saturated animal fat) over the previous 14 days. All rats received ghrelin and vehicle solution in a cross over design with one day washout between injections. **P<0.01, ***P<0.001.</p