The pharmacology and function of receptors for short-chain fatty acids

Despite some blockbuster G protein–coupled receptor (GPCR) drugs, only a small fraction (∼15%) of the more than 390 nonodorant GPCRs have been successfully targeted by the pharmaceutical industry. One way that this issue might be addressed is via translation of recent deorphanization programs that have opened the prospect of extending the reach of new medicine design to novel receptor types with potential therapeutic value. Prominent among these receptors are those that respond to short-chain free fatty acids of carbon chain length 2–6. These receptors, FFA2 (GPR43) and FFA3 (GPR41), are each predominantly activated by the short-chain fatty acids acetate, propionate, and butyrate, ligands that originate largely as fermentation by-products of anaerobic bacteria in the gut. However, the presence of FFA2 and FFA3 on pancreatic β-cells, FFA3 on neurons, and FFA2 on leukocytes and adipocytes means that the biologic role of these receptors likely extends beyond the widely accepted role of regulating peptide hormone release from enteroendocrine cells in the gut. Here, we review the physiologic roles of FFA2 and FFA3, the recent development and use of receptor-selective pharmacological tool compounds and genetic models available to study these receptors, and present evidence of the potential therapeutic value of targeting this emerging receptor pair

Tuning and disrupting the brain—modulating the McGurk illusion with electrical stimulation

In the so-called McGurk illusion, when the synchronized presentation of the visual stimulus /ga/ is paired with the auditory stimulus /ba/, people in general hear it as /da/. Multisensory integration processing underlying this illusion seems to occur within the Superior Temporal Sulcus (STS). Herein, we present evidence demonstrating that bilateral cathodal transcranial direct current stimulation (tDCS) of this area can decrease the McGurk illusion-type responses. Additionally, we show that the manipulation of this audio-visual integrated output occurs irrespective of the number of eye-fixations on the mouth of the speaker. Bilateral anodal tDCS of the Parietal Cortex also modulates the illusion, but in the opposite manner, inducing more illusion-type responses. This is the first demonstration of using non-invasive brain stimulation to modulate multisensory speech perception in an illusory context (i.e., both increasing and decreasing illusion-type responses to a verbal audio-visual integration task). These findings provide clear evidence that both the superior temporal and parietal areas contribute to multisensory integration processing related to speech perception. Specifically, STS seems fundamental for the temporal synchronization and integration of auditory and visual inputs. For its part, posterior parietal cortex (PPC) may adjust the arrival of incoming audio and visual information to STS thereby enhancing their interaction in this latter area

Adolescent drug use escalation and de-escalation: a 3-year follow-up study [Abstract]

This study aims to assess adolescents drug use with a longitudinal perspective in order to identify factors interacting with drug use onset and course. Supported by the Swiss Federal Office of Public Health, the study was initiated in 1999 with a follow-up in 2001 and 2002. The first objective was to measure risk factors for substance use initiation. The second objective was to analyse the co-variation of substance use with environmental, social, relational, medical and psychological factors. A total of 102 adolescents, aged 14-19 years, were recruited for the study in the French-speaking part of Switzerland. Results clearly show that substance use is not a disorder per se in adolescence, but that it is part of a multidimensional complex of problems that some adolescents may encounter: increase and decrease in substance use is paralleled with an increase or decrease in the other areas. This implies that prevention of substance use should not be focused mainly on substances but should consider the adolescent's environment and significant life area

A multidisciplinary approach to study the reproductive biology of wild prawns

This work aims to provide deeper knowledge on reproductive biology of P. kerathurus in a multidisciplinary way. Upon 789 examined females, 285 were found inseminated. The logistic equation enabled to estimate the size at first maturity at 30.7 mm CL for female. The Gono-Somatic Index (GSI) showed a pronounced seasonality, ranged from 0.80 ± 0.34 to 11.24 ± 5.72. Histological analysis highlighted five stages of ovarian development. Gonadal fatty acids analysis performed with gas chromatograph evidenced a pronounced seasonal variation; total lipids varied from 1.7% dry weight (dw) in Winter, to 7.2% dw in Summer. For the first time, a chemometric approach (Principal Component Analysis) was applied to relate GSI with total lipid content and fatty acid composition of gonads. The first two components (PC1 and PC2) showed that seasonality explained about 84% of the variability of all data set. In particular, in the period February-May, lipids were characterized by high PUFAs content, that were probably utilized during embryogenesis as energy source and as constituent of the cell membranes. During the summer season, gonads accumulated saturated FAs, that will be used during embryogenesis and early larval stages, while in the cold season total lipids decreased drastically and the gonad reached a quiescent state

Évolution des comportements et des représentations sociales liés à la consommation de cannabis chez les adolescents. Résumé

La recherche, dont les résultats principaux sont décrits dans ce résumé, visait trois objectifs différents: a) mieux comprendre l'évolution de la consommation de substances durant l'adolescence; b) mesurer les représentations sociales, par rapport à la consommation, dans une population de consommateurs comparée à une population «tout-venant»; c) valider un instrument de dépistage de la consommation. L'échantillon, sur lequel porte l'observation du suivi, est représentatif d'une population de consommateurs de substances. Le suivi a été réalisé sur une période de quatre ans, l'âge des sujets variant entre 15 et 20 ans au moment du premier entretien. Pour l'évaluation des représentations sociales, une population «tout-venant» a été recrutée, afin de pouvoir comparer les attitudes et opinions des adolescents en relation avec la consommation. Enfin, pour la validation de l'instrument de screening, les deux populations, suivi et «tout-venant», ont été réunies

The Pharmacology and Function of Receptors for Short-Chain Fatty Acids

ABSTRACT Despite some blockbuster G protein-coupled receptor (GPCR) drugs, only a small fraction (∼15%) of the more than 390 nonodorant GPCRs have been successfully targeted by the pharmaceutical industry. One way that this issue might be addressed is via translation of recent deorphanization programs that have opened the prospect of extending the reach of new medicine design to novel receptor types with potential therapeutic value. Prominent among these receptors are those that respond to short-chain free fatty acids of carbon chain length 2-6. These receptors, FFA2 (GPR43) and FFA3 (GPR41), are each predominantly activated by the short-chain fatty acids acetate, propionate, and butyrate, ligands that originate largely as fermentation byproducts of anaerobic bacteria in the gut. However, the presence of FFA2 and FFA3 on pancreatic b-cells, FFA3 on neurons, and FFA2 on leukocytes and adipocytes means that the biologic role of these receptors likely extends beyond the widely accepted role of regulating peptide hormone release from enteroendocrine cells in the gut. Here, we review the physiologic roles of FFA2 and FFA3, the recent development and use of receptor-selective pharmacological tool compounds and genetic models available to study these receptors, and present evidence of the potential therapeutic value of targeting this emerging receptor pair

Chemogenetics defines receptor-mediated functions of short chain free fatty acids

Differentiating actions of short chain fatty acids (SCFAs) at free fatty acid receptor 2 (FFA2) from other free fatty acid-responsive receptors and from non-receptor-mediated effects has been challenging. Using a novel chemogenetic and knock-in strategy, whereby an engineered variant of FFA2 (FFA2-DREADD) that is unresponsive to natural SCFAs but is instead activated by sorbic acid replaced the wild-type receptor, we determined that activation of FFA2 in differentiated adipocytes and colonic crypt enteroendocrine cells of mouse accounts fully for SCFA-regulated lipolysis and release of the incretin glucagon-like peptide-1 (GLP-1), respectively. In vivo studies confirmed the specific role of FFA2 in GLP-1 release and also demonstrated a direct role for FFA2 in accelerating gut transit. Thereby, we establish the general principle that such a chemogenetic knock-in strategy can successfully define novel G-protein-coupled receptor (GPCR) biology and provide both target validation and establish therapeutic potential of a ‘hard to target’ GPCR

Distributed temperature sensor system based on Raman scattering using correlation-codes

A distributed sensor system employing spontaneous Raman scattering with use of correlation-coding techniques and a single-detector scheme is discussed and experimentally characterised. A sensing distance of up to 8 km is achieved with high spatial and temperature resolutions; use of correlation-coding significantly reduces measurement time and allows use of low-power laser sources