Studying food reward and motivation in humans

A key challenge in studying reward processing in humans is to go beyond subjective self-report measures and quantify different aspects of reward such as hedonics, motivation, and goal value in more objective ways. This is particularly relevant for the understanding of overeating and obesity as well as their potential treatments. In this paper are described a set of measures of food-related motivation using handgrip force as a motivational measure. These methods can be used to examine changes in food related motivation with metabolic (satiety) and pharmacological manipulations and can be used to evaluate interventions targeted at overeating and obesity. However to understand food-related decision making in the complex food environment it is essential to be able to ascertain the reward goal values that guide the decisions and behavioral choices that people make. These values are hidden but it is possible to ascertain them more objectively using metrics such as the willingness to pay and a method for this is described. Both these sets of methods provide quantitative measures of motivation and goal value that can be compared within and between individuals

Analysis of Parametric Oscillatory Instability in Power Recycled LIGO Interferometer

We present the analysis of a nonlinear effect of parametric oscillatory instability in power recycled LIGO interferometer with the Fabry-Perot (FP) cavities in the arms. The basis for this effect is the excitation of the additional (Stokes) optical mode and the mirror elastic mode, when the optical energy stored in the main FP cavity main mode exceeds the certain threshold and the frequencies are related so that sum of frequencies of Stokes and elastic modes are approximately equal to frequencyof main mode. The presence of anti-Stokes modes (with frequency approximately equal to sum of frequencies of main and elastic modes) can depress parametric instability. However, it is very likely that the anti-Stokes modes will not compensate the parametric instability completely.Comment: 9 pages, 2 figures. submitted to Physics Letters

A Metabolomic Signature of Acute Caloric Restriction

Context: The experimental paradigm of acute caloric restriction followed by refeeding can be used to study the homeostatic mechanisms that regulate energy homeostasis, which are relevant to understanding the adaptive response to weight loss. Objective: Metabolomics, the measurement of hundreds of small molecule metabolites, their precursors, derivatives, and degradation products, has emerged as a useful tool for the study of physiology and disease and was used here to study the metabolic response to acute caloric restriction. Participants, Design and Setting: We used four ultra high performance liquid chromatography-tandem mass spectrometry methods to characterize changes in carbohydrates, lipids, amino acids and steroids in eight normal weight men at baseline, after 48 hours of caloric restriction (CR; 10% of energy requirements) and after 48 hours of ad libitum refeeding in a tightly-controlled environment. Results: We identified a distinct metabolomic signature associated with acute CR characterized by the expected switch from carbohydrate to fat utilization with increased lipolysis and beta-fatty acid oxidation. We found an increase in omega-fatty acid oxidation and levels of endocannabinoids which are known to promote food intake. These changes were reversed with refeeding. Several plasmalogen phosphatidylethanolamines (endogenous anti-oxidants) significantly decreased with CR (all p≤0.0007). Additionally, 48 acute CR was associated with an increase in the branched chain amino acids (all p≤1.4x10-7) and dehydroepiandrosterone sulfate (p=0.0006). Conclusions We identified a distinct metabolomic signature associated with acute CR. Further studies are needed to characterise the mechanisms that mediate these changes and their potential contribution to the adaptive response to dietary restriction.This work was supported by the Wellcome Trust (to I.S.F.), the NIHR Cambridge Biomedical Research Centre, the European Research Council, the Bernard Wolfe Health Neuroscience Fund (all to I.S.F.), the Swiss National Science Foundation (P3SMP3-155318, PZ00P3-167826, to T.H.C.), and the Uehara Memorial Foundation (to T.S.). This work was supported by the NIHR Rare Diseases Translational Research Collaboration and the NeuroFAST consortium, which is funded by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 245009

Oxytocin administration suppresses hypothalamic activation in response to visual food cues

The aim of this study was to use functional neuroimaging to investigate whether oxytocin modulates the neural response to visual food cues in brain regions involved in the control of food intake. Twenty-four normal weight volunteers received intranasal oxytocin (24 IU) or placebo in a double-blind, randomized crossover study. Measurements were made forty-five minutes after dosing. On two occasions, functional MRI (fMRI) scans were performed in the fasted state; the blood oxygen level-dependent (BOLD) response to images of high-calorie foods versus low-calorie foods was measured. Given its critical role in eating behaviour, the primary region of interest was the hypothalamus. Secondary analyses examined the parabrachial nuclei and other brain regions involved in food intake and food reward. Intranasal oxytocin administration suppressed hypothalamic activation to images of high-calorie compared to low-calorie food (P = 0.0125). There was also a trend towards suppression of activation in the parabrachial nucleus (P = 0.0683). No effects of intranasal oxytocin were seen in reward circuits or on ad libitum food intake. Further characterization of the effects of oxytocin on neural circuits in the hypothalamus is needed to establish the utility of targeting oxytocin signalling in obesity

From monogenic to polygenic obesity: recent advances

The heritability of obesity and body weight in general is high. A small number of confirmed monogenic forms of obesity—the respective mutations are sufficient by themselves to cause the condition in food abundant societies—have been identified by molecular genetic studies. The elucidation of these genes, mostly based on animal and family studies, has led to the identification of important pathways to the disorder and thus to a deeper understanding of the regulation of body weight. The identification of inborn deficiency of the mostly adipocyte-derived satiety hormone leptin in extremely obese children from consanguineous families paved the way to the first pharmacological therapy for obesity based on a molecular genetic finding. The genetic predisposition to obesity for most individuals, however, has a polygenic basis. A polygenic variant by itself has a small effect on the phenotype; only in combination with other predisposing variants does a sizeable phenotypic effect arise. Common variants in the first intron of the ‘fat mass and obesity associated’ gene (FTO) result in an elevated body mass index (BMI) equivalent to approximately +0.4 kg/m² per risk allele. The FTO variants were originally detected in a genome wide association study (GWAS) pertaining to type 2 diabetes mellitus. Large meta-analyses of GWAS have subsequently identified additional polygenic variants. Up to December 2009, polygenic variants have been confirmed in a total of 17 independent genomic regions. Further study of genetic effects on human body weight regulation should detect variants that will explain a larger proportion of the heritability. The development of new strategies for diagnosis, treatment and prevention of obesity can be anticipated

Two novel missense mutations in G protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism

It has recently been shown that loss-of-function mutations of the G protein-coupled receptor (GPR) 54 lead to isolated hypogonadotropic hypogonadism (IHH) in mice and humans. Such mutations are thought to be rare, even within the clinical IHH population, and only a handful of alleles have been described, making further screening of IHH populations imperative. We examined the genes encoding GPR54 and its putative endogenous ligand, kisspeptin-1, for mutations in a cohort of 30 patients with normosmic HH or delayed puberty. One subject with HH, of mixed Turkish-Cypriot and Afro-Caribbean ancestry, was found to be a compound heterozygote for two previously undescribed missense mutations in GPR54: cysteine 223 to arginine (C223R) in the fifth transmembrane helix and arginine 297 to leucine (R297L) in the third extracellular loop. Assessed in vitro using a previously described sensitive signaling assay in cells stably expressing GPR54, the C223R variant was found to exhibit profoundly impaired signaling, whereas the R297L variant showed a mild reduction in ligand-stimulated activity across the ligand dose range. These novel mutations provide further evidence that human HH may be caused by loss-of-function mutations in GPR54

Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.

This is the final version. Available from This is the final version. Available from [publisher] via the DOI in this record.  via the DOI in this record. SCOOP and INTERVAL WES data are accessible from EGA (EGAS00001000124 and EGAS00001000825). All other data are available in the manuscript or the supplementary materialsThe discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.Wellcome Trust Senior Investigator AwardWellcome TrustCRU