Impact of obesity on taste receptor expression in extra-oral tissues: emphasis on hypothalamus and brainstem OPEN

Sweet perception promotes food intake, whereas that of bitterness is inhibitory. Surprisingly, the expression of sweet G protein-coupled taste receptor (GPCTR) subunits (T1R2 and T1R3) and bitter GPCTRs (T2R116, T2R118, T2R138 and T2R104), as well as the α-subunits of the associated signalling complex (αGustducin, Gα14 and αTransducin), in oral and extra-oral tissues from lean and obese mice, remains poorly characterized. We focused on the impact of obesity on taste receptor expression in brain areas involved in energy homeostasis, namely the hypothalamus and brainstem. We demonstrate that many of the GPCTRs and α-subunits are co-expressed in these tissues and that obesity decreases expression of T1R3, T2R116, Gα14, αTrans and TRPM5. In vitro high levels of glucose caused a prominent down-regulation of T1R2 and Gα14 expression in cultured hypothalamic neuronal cells, leptin caused a transient down-regulation of T1R2 and T1R3 expression. Intriguingly, expression differences were also observed in other extra-oral tissues of lean and obese mice, most strikingly in the duodenum where obesity reduced the expression of most bitter and sweet receptors. In conclusion, obesity influences components of sweet and bitter taste sensing in the duodenum as well as regions of the mouse brain involved in energy homeostasis, including hypothalamus and brainstem. Taste perception is an important aspect in the control of food intake. Taste is mainly sensed by taste receptor containing cells located in the taste buds distributed in the different gustatory epitheliums in the tongue, palate, larynx and epiglottis. The sensing of sweet, umami and bitter taste is mediated by two G protein-coupled taste receptor (GPCTR) families: the T1R family, which is mainly involved in the sensing of sweet and umami taste-like signalling molecules and the T2R family, involved in the sensing of bitter taste-like signalling molecules 1 . The T1R family consists of three different GPCTRs that generate at least two heterodimeric receptors: T1R1+T1R3 associated with umami taste sensing and T1R2+T1R3 associated with sweet taste sensing 1,2 . In mice the T2R family consists of at least 36 distinct taste receptor members, which individually sense bitter taste like molecules 3 . The human T2R16 selectively recognizes β-glucopyranosides 4 , while the human T2R38 recognizes phenylthiocarbamide (PTC) 5 . The functional importance of the latter two human receptors was demonstrated by the finding that overexpression of either receptor in mice increases food avoidance 6 . Although the T1R and T2R receptor families drive different taste perceptions, they share similar downstream G protein-coupled signalling pathways. In particular, the taste specific α-subunit of the G protein α-gustducin (αGust) is coupled to both receptor families and has been described as critical for sweet and bitter taste responses 7 . Nevertheless, αGust knockout animals still preserve a moderate sensitivity to some bitter compounds and to sweet compounds in higher mM concentration

Explaining variation in Down's syndrome screening uptake: comparing the Netherlands with England and Denmark using documentary analysis and expert stakeholder interviews.

Background: The offer of prenatal Down’s syndrome screening is part of routine antenatal care in most of Europe; however screening uptake varies significantly across countries. Although a decision to accept or reject screening is a personal choice, it is unlikely that the widely differing uptake rates across countries can be explained by variation in individual values alone. The aim of this study was to compare Down’s syndrome screening policies and programmes in the Netherlands, where uptake is relatively low ( 90% respectively), in an attempt to explain the observed variation in national uptake rates. Methods: We used a mixed methods approach with an embedded design: a) documentary analysis and b) expert stakeholder analysis. National central statistical offices and legal documents were studied first to gain insight in demographic characteristics, cultural background, organization and structure of healthcare followed by documentary analysis of primary and secondary sources on relevant documents on DSS policies and programme. To enhance interpretation of these findings we performed in-depth interviews with relevant expert stakeholders. Results: There were many similarities in the demographics, healthcare systems, government abortion legislation and Down’s syndrome screening policy across the studied countries. However, the additional cost for Down’s syndrome screening over and above standard antenatal care in the Netherlands and an emphasis on the ‘right not to know’ about screening in this country were identified as potential explanations for the ‘low’ uptake rates of Down’s syndrome screening in the Netherlands. The social context and positive framing of the offer at the service delivery level may play a role in the relatively high uptake rates in Denmark. Conclusions: This paper makes an important contribution to understanding how macro-level demographic, social and healthcare delivery factors may have an impact on national uptake rates for Down’s syndrome screening. It has suggested a number of policy level and system characteristics that may go some way to explaining the relatively low uptake rates of Down’s syndrome screening in the Netherlands when compared to England and Denmark

Quality indicators for Dutch Down Syndrome screening laboratories 2013

De zogeheten combinatietesten die de zeven Nederlandse screeningslaboratoria op downsyndroom uitvoeren, zijn in 2013 volgens de kwaliteitseisen uitgevoerd. De laboratoria voldeden in het algemeen aan de landelijke kwaliteitseisen en aan het internationale kwaliteitsprogramma UK-NEQAS. Dit blijkt uit een evaluatie van het RIVM. Hiermee wordt voldaan aan de opdracht van het ministerie van VWS om de kwaliteit van de combinatietest te bewaken. De screening op het syndroom van Down is sinds 1 januari 2007 voor iedereen beschikbaar in een landelijk screeningsprogramma. Later is daar de screening op de syndromen van Edwards en Patau aan toegevoegd. Voor de screening worden een hormoon en een eiwit gemeten en wordt een nekplooimeting uitgevoerd. In 2013 zijn in totaal 52263 screeningstests uitgevoerd. Dat jaar liet in Nederland 29,9 procent van de zwangeren een dergelijke test uitvoeren. Dat is iets meer dan in 2009-2012. De laboratoria voeren alle bloedanalyses uit. De kansberekening op basis van die bloedanalyse kan door het laboratorium maar ook door een deel van de echocentra in Nederland worden uitgevoerd. In 46 procent van de afgenomen combinatietesten heeft de berekening van de kans op syndroom van Down, Edwards en Patau bij de laboratoria plaatsgevonden. Voor deze evaluatie waren alleen de gegevens over de kansberekening van de laboratoria beschikbaar. De leeftijd waarop de test het vaakst wordt afgenomen varieert van 31,8 tot 33,5 jaar (mediane leeftijd). Het aantal zwangeren dat volgens de screeningtest een verhoogde kans heeft op een kind met het syndroom van Down verschilt iets per laboratorium (tussen de 5,1 en 6,8 procent). Deze verschillen ontstaan onder andere doordat de gemiddelde leeftijd van zwangeren die voor deze screeningtests kiezen per regio iets verschiltIn 2013, the so-called combined tests performed by the seven Dutch screening laboratories to detect Down syndrome were performed according to the quality requirements. In general, the laboratories met the national quality requirements and the requirements of the international UK-NEQAS quality programme. These are the findings of an assessment by RIVM. This meets the directive of the Dutch Ministry of Health, Welfare and Sport to ensure the quality of the combined test. Since 1 January 2007, the screening for Down syndrome has been available to all pregnant women, as part of a national screening programme. The screening for Edwards' syndrome and Patau's syndrome was added to the programme later. The screening is based on the measurements of a particular hormone and protein level, combined with an ultrasound scan measuring nuchal translucency. In 2013, a total of 52,263 combined tests were performed. In that year, 29.9 percent of all pregnant women in the Netherlands took part in such a test. This is slightly more than in 2009-2012. The laboratories perform all blood analyses. The risk calculation based on blood analysis can be performed by the laboratory, but some of the ultrasound centres in the Netherlands are also capable of performing these calculations. In 46 percent of the performed combined tests, the risk calculation for Down syndrome, Edwards' syndrome and Patau's syndrome took place in the laboratories. This evaluation is only based on the risk calculation as performed by the laboratories. The age at which most tests were performed, varies from 31.8 to 33.5 years (median age). The number of pregnant women that have an increased risk of a child with Down syndrome varies slightly per laboratory (between 5.1 and 6.8 percent). These differences are caused, among other things, by the average age of participating pregnant women, which differs slightly per region.Ministerie van VW

A Classification Framework for Storage and Retrieval of Context

Abstract. An increasingly important requirement for mobile and pervasive systems is the capability to adapt at runtime to a changing context; they must be context-aware. Much current work in this field focuses on application-specific solutions and ad-hoc approaches, and the lack of conceptual models for the design of context-aware systems hinders the development of more general and complex systems. In this paper we present a classification framework for the storage and retrieval of context, which supports the development of contextaware systems. We demonstrate the usefulness of the framework by modeling a number of context-aware systems. 1

Comparison of Different Blood Collection, Sample Matrix, and Immunoassay Methods in a Prenatal Screening Setting

We compared how measurements of pregnancy-associated plasma protein A (PAPP-A) and the free beta subunit of human chorionic gonadotropin (fβ-hCG) in maternal blood are influenced by different methods for blood collection, sample matrix, and immunoassay platform. Serum and dried blood spots (DBS) were obtained by venipuncture and by finger prick of 19 pregnant women. PAPP-A and fβ-hCG from serum and from DBS were measured by conventional indirect immunoassay on an AutoDELFIA platform and by antibody microarray. We compared methods based on the recoveries for both markers as well as marker levels correlations across samples. All method comparisons showed high correlations for both marker concentrations. Recovery levels of PAPP-A from DBS were 30% lower, while those of fβ-hCG from DBS were 50% higher compared to conventional venipuncture serum. The recoveries were not affected by blood collection or immunoassay method. The high correlation coefficients for both markers indicate that DBS from finger prick can be used reliably in a prenatal screening setting, as a less costly and minimally invasive alternative for venipuncture serum, with great logistical advantages. Additionally, the use of antibody arrays will allow for extending the number of first trimester screening markers on maternal and fetal health

Impact of obesity on taste receptor expression in extra-oral tissues: emphasis on hypothalamus and brainstem

Sweet perception promotes food intake, whereas that of bitterness is inhibitory. Surprisingly, the expression of sweet G protein-coupled taste receptor (GPCTR) subunits (T1R2 and T1R3) and bitter GPCTRs (T2R116, T2R118, T2R138 and T2R104), as well as the α-subunits of the associated signalling complex (αGustducin, Gα14 and αTransducin), in oral and extra-oral tissues from lean and obese mice, remains poorly characterized. We focused on the impact of obesity on taste receptor expression in brain areas involved in energy homeostasis, namely the hypothalamus and brainstem. We demonstrate that many of the GPCTRs and α-subunits are co-expressed in these tissues and that obesity decreases expression of T1R3, T2R116, Gα14, αTrans and TRPM5. In vitro high levels of glucose caused a prominent down-regulation of T1R2 and Gα14 expression in cultured hypothalamic neuronal cells, leptin caused a transient down-regulation of T1R2 and T1R3 expression. Intriguingly, expression differences were also observed in other extra-oral tissues of lean and obese mice, most strikingly in the duodenum where obesity reduced the expression of most bitter and sweet receptors. In conclusion, obesity influences components of sweet and bitter taste sensing in the duodenum as well as regions of the mouse brain involved in energy homeostasis, including hypothalamus and brainstem

Predictive Performance of a Seven-Plex Antibody Array in Prenatal Screening for Down Syndrome

We evaluated the use of multiplex antibody array methodology for simultaneous measurement of serum protein markers for first trimester screening of Down Syndrome (DS) and other pregnancy outcomes such as preeclampsia. For this purpose, we constructed an antibody array for indirect (“sandwich”) measurement of seven serum proteins: pregnancy-associated plasma protein-A (PAPP-A), free beta subunit of human chorionic gonadotropin (fβ-hCG), alpha-fetoprotein (AFP), angiopoietin-like 3 (ANGPTL3), epidermal growth factor (EGF), insulin-like growth factor 2 (IGFII), and superoxide dismutase 1 (SOD1). This array was tested using 170 DS cases and 510 matched controls drawn during the 8th–13th weeks of pregnancy. Data were used for prediction modelling and compared to previously obtained AutoDELFIA immunoassay data for PAPP-A and fβ-hCG. PAPP-A and fβ-hCG serum concentrations obtained using antibody arrays were highly correlated with AutoDELFIA data. Moreover, DS prediction modeling using (log-MoMmed) antibody array and AutoDELFIA data gave comparable results. Of the other markers, AFP and IGFII showed significant changes in concentration, although adding these markers to a prediction model based on prior risk, PAPP-A and fβ-hCG did not improve the predictive performance. We conclude that implementation of antibody arrays in a prenatal screening setting is feasible but will require additional first trimester screening markers

External validation of prognostic models to predict risk of gestational diabetes mellitus in one Dutch cohort : prospective multicentre cohort study

OBJECTIVE: To perform an external validation and direct comparison of published prognostic models for early prediction of the risk of gestational diabetes mellitus, including predictors applicable in the first trimester of pregnancy. DESIGN: External validation of all published prognostic models in large scale, prospective, multicentre cohort study. SETTING: 31 independent midwifery practices and six hospitals in the Netherlands. PARTICIPANTS: Women recruited in their first trimester (<14 weeks) of pregnancy between December 2012 and January 2014, at their initial prenatal visit. Women with pre-existing diabetes mellitus of any type were excluded. MAIN OUTCOME MEASURES: Discrimination of the prognostic models was assessed by the C statistic, and calibration assessed by calibration plots. RESULTS: 3723 women were included for analysis, of whom 181 (4.9%) developed gestational diabetes mellitus in pregnancy. 12 prognostic models for the disorder could be validated in the cohort. C statistics ranged from 0.67 to 0.78. Calibration plots showed that eight of the 12 models were well calibrated. The four models with the highest C statistics included almost all of the following predictors: maternal age, maternal body mass index, history of gestational diabetes mellitus, ethnicity, and family history of diabetes. Prognostic models had a similar performance in a subgroup of nulliparous women only. Decision curve analysis showed that the use of these four models always had a positive net benefit. CONCLUSIONS: In this external validation study, most of the published prognostic models for gestational diabetes mellitus show acceptable discrimination and calibration. The four models with the highest discriminative abilities in this study cohort, which also perform well in a subgroup of nulliparous women, are easy models to apply in clinical practice and therefore deserve further evaluation regarding their clinical impact

TUB gene expression in hypothalamus and adipose tissue and its association with obesity in humans

BACKGROUND/OBJECTIVES: Mutations in the Tubby gene (TUB) cause late-onset obesity and insulin resistance in mice and syndromic obesity in humans. Although TUB gene function has not yet been fully elucidated, studies in rodents indicate that TUB is involved in the hypothalamic pathways regulating food intake and adiposity. Aside from the function in central nervous system, TUB has also been implicated in energy metabolism in adipose tissue in rodents. We aimed to determine the expression and distribution patterns of TUB in man as well as its potential association with obesity. SUBJECTS/METHODS: In situ hybridization was used to localize the hypothalamic regions and cells expressing TUB mRNA. Using RT-PCR, we determined the mRNA expression level of the two TUB gene alternative splicing isoforms, the short and the long transcript variants, in the hypothalami of 12 obese and 12 normal-weight subjects, and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissues from 53 severely obese and 24 non-obese control subjects, and correlated TUB expression with parameters of obesity and metabolic health. RESULTS: Expression of both TUB transcripts was detected in the hypothalamus, while only the short TUB isoform was found in both VAT and SAT. TUB mRNA was detected in several hypothalamic regions involved in body weight regulation, including the nucleus basalis of Meynert and the paraventricular, supraoptic and tuberomammillary nuclei. We found no difference in the hypothalamic TUB expression between obese and control groups, while the level of TUB mRNA was significantly lower in adipose tissue of obese subjects as compared to controls. Also, TUB expression was negatively correlated with indices of body weight and obesity in a fat-depot-specific manner. CONCLUSIONS: Our results indicate high expression of TUB in the hypothalamus, especially in areas involved in body weight regulation, and the correlation between TUB expression in adipose tissue and obesity. These findings suggest a role for TUB in human obesity.International Journal of Obesity accepted article preview online, 30 August 2017. doi:10.1038/ijo.2017.214