The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study.

Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy alcohol drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-5190457, when co-administered with alcohol. We tested the effects of PF-5190457 combined with alcohol on locomotor activity, loss-of-righting reflex (a measure of alcohol sedative actions), and on blood PF-5190457 concentrations in rats. Then, we performed a single-blind, placebo-controlled, within-subject human study with PF-5190457 (placebo/0 mg b.i.d., 50 mg b.i.d., 100 mg b.i.d.). Twelve heavy drinkers during three identical visits completed an alcohol administration session, subjective assessments, and an alcohol cue-reactivity procedure, and gave blood samples for PK/PD testing. In rats, PF-5190457 did not interact with the effects of alcohol on locomotor activity or loss-of-righting reflex. Alcohol did not affect blood PF-5190457 concentrations. In humans, all adverse events were mild or moderate and did not require discontinuation or dose reductions. Drug dose did not alter alcohol concentration or elimination, alcohol-induced stimulation or sedation, or mood during alcohol administration. Potential PD markers of PF-5190457 were acyl-to-total ghrelin ratio and insulin-like growth factor-1. PF-5190457 (100 mg b.i.d.) reduced alcohol craving during the cue-reactivity procedure. This study provides the first translational evidence of safety and tolerability of the ghrelin receptor inverse agonist PF-5190457 when co-administered with alcohol. PK/PD/behavioral findings support continued research of PF-5190457 as a potential pharmacological agent to treat alcohol use disorder.

Effects of Fruit and Vegetable Feeding Messages on Mothers and Fathers: Interactions Between Emotional State and Health Message Framing.

BACKGROUND: There is a pressing need to craft optimal public health messages promoting healthy feeding behaviors among parents. How these messages influence such feeding decisions are affected by multiple interactive factors including emotional states, message framing, and gender, but these factors have not been studied in the domain of parents' feeding of their children. PURPOSE: To evaluate the role of message framing, emotional state, and parent gender on feeding choices that parents make for their children. METHODS: In 2016-2017, 190 parents (126 mothers) of 4- to 7-year-old children were randomly assigned to an anger or fear emotion induction and read either a gain- or loss-framed message about the importance of children's fruit and vegetable (FV) consumption prior to choosing foods for their child from a virtual reality buffet. RESULTS: Mothers in an angry state who received a gain-framed message chose relatively more FV for their child in the virtual buffet, F(3, 180) = 4.77, p = .027. However, fathers in this group did not feed more FV, but rather reported greater intention to improve future FV feeding, F(3, 180) = 4.91, p = .028. CONCLUSIONS: Providing gain-framed messages to parents, particularly mothers, in an anger state may be most effective for motivating healthy dietary choices for children. CLINICAL TRIAL INFORMATION: clinicaltrials.gov NCT02622035.

Impulsive Personality Traits Mediate the Relationship Between Adult Attention-Deficit/Hyperactivity Symptoms and Alcohol Dependence Severity.

BACKGROUND: While the role of attention-deficit/hyperactivity disorder (ADHD) as a risk factor for developing alcohol use disorder (AUD) has been established, the underlying pathways connecting the two are still not fully understood. Overlapping constructs such as impulsivity may explain the increased risk for developing AUD in individuals with ADHD. METHODS: In this study, we assessed whether adult ADHD symptoms increase the odds of having a diagnosis of AUD. Furthermore, we tested whether facets of impulsivity explained the relationship between ADHD symptoms and alcohol dependence (AD) severity. RESULTS: In a logistic regression of 749 participants (464 = AD, 285 = controls), overall adult ADHD symptoms, and more specifically, symptoms of hyperactivity/restlessness and problems with self-concept, increased the odds of having a diagnosis of AD. Within the AD sample, we found that impulsivity mediated the relationship between adult ADHD symptoms and AD severity. In particular, negative and positive urgency meditated the relationship of overall adult ADHD symptoms, and symptoms of hyperactivity/restlessness and problems with self-concept with AD severity. CONCLUSIONS: These results highlight the importance of looking at cohorts of ADHD symptoms and facets of impulsivity to assess the risk of developing AUD. They also suggest potential avenues for intervention strategies in individuals with preexisting adult ADHD symptoms who are seeking treatment for AUD.

Identifying and Characterizing Subpopulations of Heavy Alcohol Drinkers Via a Sucrose Preference Test: A Sweet Road to a Better Phenotypic Characterization?

AIMS: Sweet preference in individuals with alcohol use disorder (AUD) has been associated with family history of AUD and personality traits. Therefore, testing sweet preference may help identify subpopulations of AUD individuals. SHORT SUMMARY: Sweet preference has been associated with family history of AUD and personality traits. We compared heavy drinkers based on their sweet liker status and using two cutoffs. Our findings support the role of sweet preference in heavy drinkers and point to the importance of how sweet likers are defined. METHODS: This study aimed at describing and comparing heavy drinkers based on their sweet liker status, through demographic, neuroendocrine, inflammatory, behavioral and drinking characteristics. Participants rated the pleasantness and intensity of sucrose solutions (0.05, 0.10, 0.21, 0.42 and 0.83 M). Two cutoffs were used to identify likers versus dislikers: Grouping A likers preferred 0.83 M and Grouping B likers preferred 0.83 or 0.42 M; the rest were dislikers. RESULTS: Sweet likers were 36% (n = 20) using Grouping A and 58.2% (n = 32) using Grouping B. Grouping B, but not Grouping A, sweet likers had higher BMI (P = 0.01). In Grouping B, sweet likers had higher plasma leptin and insulin concentrations and higher insulin resistance (P's < 0.05). C-reactive protein concentrations were higher in sweet likers in Grouping A (P = 0.0015) and at a trend level in Grouping B (P = 0.07). Grouping A sweet likers had higher alcohol craving (P = 0.0004). Sweet likers preferred spirits compared to nonspirits (wine and beer) across both grouping (P's < 0.05). CONCLUSIONS: These results provide further support for the role of sweet liking phenotype in identifying subpopulations of AUD individuals. These findings also point to the importance of how sweet likers are defined, therefore highlighting the need for further research.

The Validity of the Montgomery-Asberg Depression Rating Scale in an Inpatient Sample with Alcohol Dependence.

BACKGROUND: The Montgomery-Asberg Depression Rating Scale (MADRS) is commonly used to examine depressive symptoms in clinical settings, including facilities treating patients for alcohol addiction. No studies have examined the validity of the MADRS compared to an established clinical diagnostic tool of depression in this population. This study aimed to examine the following: (i) the validity of the MADRS compared to a clinical diagnosis of a depressive disorder (using the Structured Clinical Interview for DSM-IV-TR [SCID-IV-TR]) in patients seeking treatment for alcohol dependence (AD); (ii) whether the validity of the MADRS differs by type of SCID-IV-TR-based diagnosis of depression; and (iii) which items contribute to the optimal predictive model of the MADRS compared to a SCID-IV-TR diagnosis of a depressive disorder. METHODS: Individuals seeking treatment for AD and admitted to an inpatient unit were administered the MADRS at day 2 of their detoxification program. Clinical diagnoses of AD and depression were made via the SCID-IV-TR at the beginning of treatment. RESULTS: In total, 803 participants were included in the study. The MADRS demonstrated low overall accuracy relative to the clinical diagnosis of depression with an area under the receiver operating characteristic curve of 0.68. The optimal threshold for balancing sensitivity and specificity identified by the Euclidean distance was >14. This cut-point demonstrated a sensitivity of 66%, a specificity of 60%, a positive predictive value of 50%, and a negative predictive value of 75%. The MADRS performed slightly better for major depressive disorders compared to alcohol-induced depression. Items related to lassitude, concentration, and appetite slightly decreased the accuracy of the MADRS. CONCLUSIONS: The MADRS does not appear to be an appropriate substitute for a diagnostic tool among alcohol-dependent patients. The MADRS may, however, still be a useful screening tool assuming careful consideration of cut-points.

The Microbiota, the Gut and the Brain in Eating and Alcohol Use Disorders: A 'Ménage à Trois'?

AIMS: Accumulating evidence for the influence of the gut microbiota on the bidirectional communication along the gut-brain axis suggests a role of the gut microbiota in eating disorders (EDs) and alcohol and substance use disorders. The potential influence of altered gut microbiota (dysbiosis) on behaviors associated with such disorders may have implications for developing therapeutic interventions. METHODS: A systematic review of preclinical and clinical studies evaluating the gut microbiota, EDs and alcohol and substance use disorders was conducted using MEDLINE, Embase and Web of Science databases with the objective being to examine the role of the gut microbiota in behavioral correlates of these disorders. Original papers focused on the gut microbiota and potential behavioral implications were deemed eligible for consideration. RESULTS: The resulting 12 publications were limited to gut microbiota studies related to EDs and alcohol and substance use disorders. Some studies suggest that dysbiosis and gut microbial byproducts may influence the pathophysiology of EDs via direct and indirect interference with peptide hormone signaling. Additionally, dysbiosis was shown to be correlated with alcohol use disorder-related symptoms, i.e. craving, depression and anxiety. Finally, a mouse study suggests that manipulations in the gut microbiota may affect cocaine-related behaviors. CONCLUSIONS: Promising, albeit preliminary, findings suggest a potential role of the gut microbiota in behavioral correlates of EDs and alcohol and substance use disorders. SHORT SUMMARY: Preliminary evidence exists supporting the role of the gut microbiota in eating disorders and alcohol and substance use disorders, although additional investigation is needed to determine what is causative versus epiphenomenological.

Identifying eating behavior phenotypes and their correlates: A novel direction toward improving weight management interventions.

Common reports of over-response to food cues, difficulties with calorie restriction, and difficulty adhering to dietary guidelines suggest that eating behaviors could be interrelated in ways that influence weight management efforts. The feasibility of identifying robust eating phenotypes (showing face, content, and criterion validity) was explored based on well-validated individual eating behavior assessments. Adults (n = 260; mean age 34 years) completed online questionnaires with measurements of nine eating behaviors including: appetite for palatable foods, binge eating, bitter taste sensitivity, disinhibition, food neophobia, pickiness and satiety responsiveness. Discovery-based visualization procedures that have the combined strengths of heatmaps and hierarchical clustering were used to investigate: 1) how eating behaviors cluster, 2) how participants can be grouped within eating behavior clusters, and 3) whether group clustering is associated with body mass index (BMI) and dietary self-efficacy levels. Two distinct eating behavior clusters and participant groups that aligned within these clusters were identified: one with higher drive to eat and another with food avoidance behaviors. Participants' BMI (p = 0.0002) and dietary self-efficacy (p < 0.0001) were associated with cluster membership. Eating behavior clusters showed content and criterion validity based on their association with BMI (associated, but not entirely overlapping) and dietary self-efficacy. Identifying eating behavior phenotypes appears viable. These efforts could be expanded and ultimately inform tailored weight management interventions.

Drivers of overweight mothers' food choice behaviors depend on child gender.

BACKGROUND: National data suggest a higher prevalence of obesity among boys. One possible cause could be the food choices made by parents on behalf of their children. OBJECTIVES: This study sought to determine whether and how mothers' food choices for their children differ by child gender and to understand the drivers of these differences. DESIGN: Data were analyzed from a randomized controlled trial conducted using a virtual reality-based buffet restaurant. Overweight mothers filled out questionnaires and received an information module. They were then immersed in a virtual buffet restaurant to select a lunch for their 4- to 5-year-old child. RESULTS: Of the 221 overweight mothers recruited, 55% identified their daughters as the child for whom they would be choosing the food. The caloric content of boys' meals was 43 calories higher than girls' (p = .015). This difference was due to extra calories from the less healthy food category (p = .04). Multivariate analyses identified more predictors of calorie choices for daughters' than sons' meals. Predictors of calories chosen for girls included: having both biological parents overweight (ß = 0.26; p = .003), mother's weight (ß = 0.17; p = .05), mother's education (ß = -0.28; p = .001), her restriction of her child's food intake (ß = -0.20; p = .02), and her beliefs about the importance of genetics in causing obesity (ß = 0.19; p = .03). Mother's weight was the sole predictor of boys' meal calories (ß = 0.20; p = .04). CONCLUSIONS: Differences in dietary choices made for young girls and boys may contribute to lifelong gender differences in eating patterns. A better understanding of differences in feeding choices made for girls versus boys could improve the design of childhood obesity prevention interventions.

'Just a pinch of salt'. An experimental comparison of the effect of repeated exposure and flavor-flavor learning with salt or spice on vegetable acceptance in toddlers.

Children's vegetable intake is below the recommended amounts. No studies to date have tested the relevance of using salt or spices to increase children's vegetable acceptance. Our objective was to compare the effect of repeated exposure (RE) and of flavor-flavor learning (FFL) on toddlers' acceptance of a non-familiar vegetable. Two unconditioned stimuli were used: salt and a salt-associated spice. Toddlers attending six nurseries were assigned to 3 groups in a between subject design. Groups were exposed 8 times to a basic salsify puree (0.2% salt w/w; RE group; n = 47), a salty salsify puree (0.5% salt w/w; FFL-Salt group; n = 54) or a spiced salsify puree (0.2% salt and 0.02% nutmeg w/w; FFL-Nutmeg group; n = 50). Acceptance (intake and liking) of the target vegetable (basic salsify puree) and of a control vegetable (carrot puree) was evaluated at pre-exposure, at each exposure of the learning period, at post-exposure, and at 1, 3 and 6 months after exposure. In all groups, intake of the target vegetable increased from pre- to post-exposure. This increase was significantly higher in the RE group (64 ± 11 g) than in the FFL-Salt group (23 ± 11 g) and marginally higher than in the FFL-Nutmeg group (36 ± 11 g). No difference between groups was observed on the increase in liking of the target vegetable from pre- to post-exposure. The increase of the target vegetable intake was still observed after 6 months for all groups. Thus, repeated exposure appears to be the simplest choice to increase vegetable intake on the short and long term in toddlers.

Gut microbial diversity and functional characterization in people with alcohol use disorder: A case-control study.

Individuals with Alcohol Use Disorder (AUD) typically have comorbid chronic health conditions, including anxiety and depression disorders, increased sleep disruption, and poor nutrition status, along with gut microbial dysbiosis. To better understand the effects of gut dysbiosis previously shown in individuals with AUD, gut microbiome and metabolome were investigated between three cohorts. Two groups of individuals with AUD included treatment-seeking newly abstinent for at least six weeks (AB: N = 10) and non-treatment-seeking currently drinking (CD: N = 9) individuals. The third group was age, gender, and BMI-matched healthy controls (HC: N = 12). Deep phenotyping during two weeks of outpatient National Institutes of Health Clinical Center visits was performed, including clinical, psychological, medical, metabolic, dietary, and experimental assessments. Alpha and beta diversity and differential microbial taxa and metabolite abundance of the gut microbiome were examined across the three groups. Metabolites derived from the lipid super-pathway were identified to be more abundant in the AB group compared to CD and HC groups. The AB individuals appeared to be most clinically different from CD and HC individuals with respect to their gut microbiome and metabolome. These findings highlight the potential long-term effects of chronic alcohol use in individuals with AUD, even during short-term abstinence.

Eating a rainbow. Introducing vegetables in the first years of life in 3 European countries.

Low vegetable consumption in children is a concern in many EU countries, fewer than one fifth of children in Europe consume the WHO recommended amounts. Systematic studies demonstrate that experience with a variety of vegetables early in childhood can promote later consumption as early dietary habits often track into adulthood. This study examined pre-school children's experience with vegetables across three European countries in order to assess cultural differences, effects of age and culinary practices. Mothers of pre-school children (N=234) in the UK (N=71), Denmark (N=93) and France (N=70) completed a survey assessing parental and infant familiarity, frequency of offering and liking for 56 vegetables as well as preparation techniques for these vegetables. Analyses revealed that although children aged 25-36 months had been introduced to the greatest number of vegetables, children aged 6-12 months were offered vegetables more frequently and had a higher reported liking for these vegetables. UK children's liking was related to frequency of maternal intake and frequency of offering. Denmark had introduced the greatest number of vegetables and offered vegetables more frequently than both the UK and France. Choice of preparation methods differed between countries while choice of seasonings was similar. Results suggest increasing variety and frequency of vegetable offering between 6 and 12 months, when children are most receptive, may promote vegetable consumption in children.

The impact of salt, fat and sugar levels on toddler food intake.

Understanding the early determinants of food intake, in particular the role of food sensory quality, is a necessary step to improve the prevention of unhealthy food habits. However, the extent to which food intake varies according to salt, fat and sugar content is imperfectly known. The present study aimed at evaluating whether toddler food intake varied during lunches or snacks in which salt, fat or sugar contents had been modified in common foods. Seventy-four children (30 (se 0·5) months old) participated in the study in their usual day-care centres. Every other week, they were served lunches composed, among other items, of green beans and pasta with varying salt (0, 0·6 and 1·2 % added salt) or fat (0, 2·5 and 5 % added butter) levels and afternoon snacks composed of fruit purée varying in sugar level (0, 5 and 10 % added sugar). During each meal, children could eat as much as they wanted from the target foods. Each food was weighed before and after the meal. Salt level had a positive impact on the intake of the target foods. On the contrary, no impact of added fat or added sugar levels was observed. This implies that fat and sugar addition could be avoided in foods for children without having an impact on palatability, allowing the energy density of children's diet to be limited. Salt addition should be limited, but its suppression in vegetables, whose intake is to be promoted, should be considered cautiously.

Cognitive and affective factors linking mothers' perceived weight history to child feeding.

BACKGROUND/OBJECTIVES: To explore whether mothers' lifetime experiences with their own weight status and related cognitive and affective factors influence child feeding behavior. SUBJECTS/METHODS: Overweight mothers (N = 221) of 4-5 year olds recalled their weight at four time points, and were grouped into weight history trajectories: recently overweight, always overweight, and steady-gain-obese. Objective food choice behavior was assessed in a virtual reality buffet and subjective food restriction for the index child was assessed using a psychometric measure. RESULTS: Mothers' observed food choice was not associated with weight trajectory, but mothers who spent more time being overweight and who weighed more at present were more restrictive of their child's eating. Mothers' concern about child weight increased with more time spent being overweight. Concern for child weight and mothers' body guilt differentially mediated the relationships between weight trajectories and perceived feeding restriction. CONCLUSIONS: Considering mothers' lifetime weight experiences may suggest that parental influences on child feeding are amenable to intervention that would otherwise be obscured by static weight measures.

Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment.

Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the nervous system, plays an important role in biobehavioral processes that regulate alcohol seeking, food intake, and stress response. The metabotropic GABA-B receptor has been investigated as a potential therapeutic target for alcohol use disorder, by using orthosteric agonists (e.g., baclofen) and positive allosteric modulators. Whether and how pharmacological manipulation of the GABA-B receptor, in combination with alcohol intake, may affect feeding- and stress-related neuroendocrine pathways remains unknown. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals received baclofen (30 mg/day) or placebo in a naturalistic outpatient setting for one week, and then performed a controlled laboratory experiment which included alcohol cue-reactivity, fixed-dose priming, and self-administration procedures. Blood samples were collected, and the following neuroendocrine markers were measured: ghrelin, leptin, amylin, glucagon-like peptide-1 (GLP-1), insulin, prolactin, thyroid-stimulating hormone, growth hormone, cortisol, and adrenocorticotropic hormone (ACTH). During the outpatient phase, baclofen significantly increased blood concentrations of acyl-ghrelin (p = 0.01), leptin (p = 0.01), amylin (p = 0.004), and GLP-1 (p = 0.02). Significant drug × time-point interaction effects for amylin (p = 0.001) and insulin (p = 0.03), and trend-level interaction effects for GLP-1 (p = 0.06) and ACTH (p = 0.10) were found during the laboratory experiment. Baclofen, compared to placebo, had no effect on alcohol drinking in this study (p's ≥ 0.05). Together with previous studies, these findings shed light on the role of the GABAergic system and GABA-B receptors in the shared neurobiology of alcohol-, feeding-, and stress-related behaviors.

Beliefs about genetic influences on eating behaviors: Characteristics and associations with weight management confidence.

INTRODUCTION: The development of precision approaches for customized health interventions is a promising application of genomic discovery. To optimize such weight management interventions, target audiences will need to be engaged in research and implementation efforts. Investigation into approaches that engage these audiences will be required to ensure that genomic information, particularly with respect to genomic influences on endophenotypes like eating behavior, is understood and accepted, and not associated with unintended adverse outcomes. We took steps to characterize healthy individuals' beliefs about genetic influences on eating behavior. METHODS: Data were collected via online survey from 261 participants selected at random from a database. RESULTS: Respondents infrequently spontaneously identified eating behavior-related factors as running in families. However, those who perceived themselves as overweight and perceived a family history of overweight were more likely to attribute eating behavior to genetics on closed-ended assessments, ß=0.252, p=0.039. Genetic attributions for eating behaviors were associated with lower confidence in ability to control eating and weight, ß=-0.119, p=0.035. CONCLUSIONS: These exploratory findings shed light on beliefs about genetic influences on eating, a behavioral trait (rather than a disease). This investigation can inform future health intervention efforts.

Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon-like peptide-1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses.

BACKGROUND: Food intake and use of drugs of abuse like cocaine share common central and peripheral physiological pathways. Appetitive hormones play a major role in regulating food intake; however, little is known about the effects of acute cocaine administration on the blood concentrations of these hormones in cocaine users. METHODS: We evaluated serum concentrations of six appetitive hormones: ghrelin (total and acyl-ghrelin), amylin, glucagon-like peptide-1 (GLP-1), insulin, leptin and peptide YY (PYY), as well as acute cardiorespiratory and subjective responses of 8 experienced cocaine users who received 25mg intravenous (IV) cocaine. RESULTS: Serum concentrations of GLP-1 (p=0.014) and PYY (p=0.036) were significantly decreased one hour following IV cocaine administration; there was a trend towards a decrease for insulin (p=0.055) and amylin (p=0.063) concentrations, while no significant IV cocaine effect was observed for ghrelin (total or acyl-ghrelin) or leptin concentrations (p's≫>0.5). We also observed associations between hormone concentrations acutely affected by IV cocaine (GLP-1, PYY, insulin, amylin) and some cocaine-related cardiorespiratory and subjective responses (e.g., increased heart and respiratory rates; feeling high and anxious). DISCUSSION: These findings show a significant effect of acute IV cocaine administration on some appetitive hormones and suggest potential associations between these hormones and cocaine-related cardiorespiratory and subjective responses. Additional research is needed to further investigate the potential mechanisms underlining these associations.

Salt content impacts food preferences and intake among children.

Decreasing dietary sodium intake, which can be achieved by reducing salt content in food, is recommended. Salt contributes to the taste of foods and makes them more enjoyable. Whether a food is liked or disliked is an important determinant of food intake, especially among children. However, the role of salt in children's food acceptance has received little attention. The impact of salt content on children's hedonic rating and intake of two foods was investigated in children. Using a within-subject crossover design, we recruited 75 children (8-11 years) to participate in five lunches in their school cafeteria. The target foods were green beans and pasta. The added salt content was 0, 0.6 or 1.2 g/100 g. The children's intake (g) of all lunch items was measured. The children provided their hedonic rating of the food, a preference ranking and a saltiness ranking in the laboratory. Children could rank the foods according to salt content, and they preferred the two saltier options. A food-specific effect of salt content on intake was observed. Compared to the intermediate level (0.6 g salt/100 g), not adding salt decreased green bean intake (-21%; p = 0.002), and increasing the salt content increased pasta intake (+24%; p<0.0001). Structural Equation Modeling was used to model the relative weights of the determinants of intake. It showed that the primary driver of food intake was the child's hunger; the second most important factor was the child's hedonic rating of the food, regardless of its salt content, and the last factor was the child's preference for the particular salt content of the food. In conclusion, salt content has a positive and food-specific effect on intake; it impacted food preferences and intake differently in children. Taking into account children's preferences for salt instead of their intake may lead to excessive added salt.