The impact of periodontitis and periodontal treatment on rheumatoid arthritis outcomes: an exploratory clinical trial.

OBJECTIVE: Studies suggest rheumatoid arthritis (RA) patients could benefit from periodontal treatment. However, published data are inconsistent, and there is a need for better-controlled research. Our study aims to address these limitations. METHODS: In this exploratory randomised delayed-start study, 22 RA patients with moderate/severe periodontitis were subjected to full-mouth debridement. Periodontal and rheumatological assessments, including measuring anti-cyclic citrullinated peptide 2 (CCP2) IgG levels, were performed at baseline (V1), 2 months (V2) and 6 months (V3) after step 1 and 2 of periodontal therapy. Primary outcome was changes in disease activity score for 28 joints (DAS28) between V2 and V1. Secondary outcomes were changes in other rheumatological or periodontal clinical parameters (V2 or V3-V1). RESULTS: RA disease activity was significantly higher in RA patients with severe periodontitis compared to moderate periodontitis at baseline, with significant positive correlations between several rheumatological and periodontal parameters. After periodontal treatment, RA patients with severe, but not moderate, periodontitis demonstrated significant improvements in DAS28 (ΔV2-V1, p = 0.042; ΔV3-V1, p = 0.001) and significant reduction in anti-CCP2 IgG levels at V3 (p = 0.032). CONCLUSION: Periodontal treatment is locally effective in patients with RA and impacts RA disease activity and anti-CCP2 antibody levels in patients with severe periodontitis. Hence, our data suggest that periodontal assessment and treatment should be integrated in the management of RA patients within a treat-to-target strategy. CLINICAL TRIAL REGISTRATION: www.isrctn.com, ISRCTN 17950307.

Photochemical Oxidation of Polyethylene Terephthalate Microplastics Adsorbed on Sand and Silica Surfaces.

The environmental contamination by plastics, microplastics, and related compounds is a major concern. While the detection and release of micro- and nanoparticles from these materials have been widely studied, the formation and release of molecules resulting from their degradation in the environment have been overlooked. This work presents a study of the products released from poly(ethylene terephthalate) (PET) irradiated as pure particles and adsorbed on silica and sand surfaces under different irradiation conditions. The role of oxygen was also evaluated. The products were identified by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-high resolution mass spectrometry (LC-HRMS). The main released molecules can be accounted for by considering the cleavage of α- and ß-bonds next to the ester moiety of the polymer chain. Volatile products such as benzene as well as monomer units of the polymer and related products were identified. In the presence of oxygen, acetic acid and products resulting from hydroxylation at the benzenic ring or at the ethyl moiety were detected. Adsorption on silica and sand has little effect on the photoproduct distributions. The irradiation at 360 nm leads to distributions similar to the ones observed at 257 nm, but the reaction rate is lower. The identified product ethylene terephthalate is a marker of PET plastics and particles and can therefore be used to evaluate the environmental contamination by this polymer material.

Environmental Markers of Plastics and Microplastics.

The slow reaction rates to chemical and photochemical degradation are well-known properties of plastics. However, large plastic surfaces exposed to environmental conditions release particles and compounds that affect ecosystems and human health. The aim of this work was to identify compounds associated with the degradation of polyethylene (PE), polystyrene (PS), and polyvinyl chloride (PVC) microplastics (markers) on silica and sand and evaluate their use to screen microplastics on natural sand. Products were identified by using targeted and untargeted LC-HRMS analysis. All polymers underwent chemical oxidation on silica. PE released dicarboxylic acids (HO2C-(CH2)n-CO2H (n = 4-30), while PS released cis/trans-chalcone, trans-dypnone, 3-phenylpropiophenone, and dibenzoylmethane. PVC released dicarboxylic acids and aromatic compounds. Upon irradiation, PE was stable while PS released the same compounds as under chemical oxidation but at lower yields. Under the above condition, PVC generated HO2C-[CH2-CHCl]n-CH2-CO2H and HO2C-[CH2-CHCl]n-CO2H (n = 2-19) dicarboxylic acids. The same products were detected on sand but at a lower concentration than on silica due to better retention within the pores. Detection of markers of PE and PS on natural sand allowed us to screen microplastics by following a targeted analysis. Markers of PVC were not detected before or after thermal/photo-oxidation due to the low release of compounds and limitations associated with surface exposure/penetration of radiation.

Disentangling the Role of the SnO Layer on the Pyro-Phototronic Effect in ZnO-Based Self-Powered Photodetectors.

Self-powered photodetectors (PDs) have been recognized as one of the developing trends of next-generation optoelectronic devices. Herein, it is shown that by introducing a thin layer of SnO film between the Si substrate and the ZnO film, the self-powered photodetector Al/Si/SnO/ZnO/ITO exhibits a stable and uniform violet sensing ability with high photoresponsivity and fast response. The SnO layer introduces a built-in electrostatic field to highly enhance the photocurrent by over 1000%. By analyzing energy diagrams of the p-n junction, the underlying physical mechanism of the self-powered violet PDs is carefully illustrated. A high photo-responsivity (R) of 93 mA W-1 accompanied by a detectivity (D*) of 3.1 × 1010 Jones are observed under self-driven conditions, when the device is exposed to 405 nm excitation laser wavelength, with a laser power density of 36 mW cm-2 and at a chopper frequency of 400 Hz. The Si/SnO/ZnO/ITO device shows an enhancement of 3067% in responsivity when compared to the Al/Si/ZnO/ITO. The photodetector holds an ultra-fast response of ≈ 2 µs, which is among the best self-powered photodetectors reported in the literature based on ZnO.

Predictors of flare in SLE patients fulfilling lupus low disease activity state: a cohort study of 292 patients with 36-month follow-up.

OBJECTIVES: The treatment target in SLE should be maintained stable by preventing flares. The objectives were to identify predictors of flare in patients attaining lupus low disease activity state (LLDAS), and to assess whether remission with no glucocorticoids is associated with lower risk of flares. METHODS: This was a cohort study of SLE patients followed in a referral centre over 3 years. Baseline was the first visit where each patient attained LLDAS. Flares up to 36 months' follow-up were identified by three instruments: revised Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA) Flare Index (r-SFI), SLEDAI-2000 (SLEDAI-2K) and SLE Disease Activity Score (SLE-DAS). Demographic, clinical and laboratory parameters at baseline were evaluated as predictors of flare, with distinct models for each flare instrument, using survival analysis with univariate followed by multivariate Cox regression. Hazard ratios (HR) were determined with 95% CI. RESULTS: A total of 292 patients fulfilling LLDAS were included. Over follow-up, 28.4%, 24.7% and 13.4% of the patients developed one or more flare, according to r-SFI, SLE-DAS and SLEDAI-2K definitions, respectively. After multivariate analysis, the predictors of SLE-DAS flares were presence of anti-U1-ribonucleoprotein (anti-U1RNP) (HR = 2.16, 95% CI 1.30, 3.59), SLE-DAS score at baseline (HR = 1.27, 95% CI 1.04, 1.54) and immunosuppressants (HR = 2.43, 95% CI 1.43, 4.09). These predictors were equally significant for r-SFI and SLEDAI-2K flares. Remitted patients with no glucocorticoids presented a lower risk of SLE-DAS flares (HR = 0.60, 95% CI 0.37, 0.98). CONCLUSION: In patients with LLDAS, anti-U1RNP, disease activity scored by SLE-DAS and SLE requiring maintenance immunosuppressants predict higher risk of flare. Remission with no glucocorticoids is associated with lower risk of flares.

New Vectors of TTX Analogues in the North Atlantic Coast: The Edible Crabs Afruca tangeri and Carcinus maenas.

Tetrodotoxin (TTX) and its analogues are naturally occurring toxins historically responsible for human poisoning fatalities in Eastern Asia. It is typically linked to the consumption of pufferfish and, to a lesser extent, marine gastropods and crabs. In the scope of a comprehensive project to understand the prevalence of emergent toxins in edible marine organisms, we report, for the first time, the detection of TTX analogues in the soft tissues of edible crabs, the European fiddler crab (Afruca tangeri) and green crab (Carcinus maenas), harvested in southern Portugal. No TTX was detected in the analyzed samples. However, three TTX analogues were detected-an unknown TTX epimer, deoxyTTX, and trideoxyTTX. These three analogues were found in the European fiddler crab while only trideoxyTTX was found in the green crab, suggesting that the accumulation of TTX analogues might be influenced by the crabs' different feeding ecology. These results highlight the need to widely monitor TTX and its analogues in edible marine species in order to provide adequate information to the European Food Safety Authority and to protect consumers.

The Design of a Glycerol Concentration Sensor Based on an LRSPP Hybrid Photonic Biosensor.

A refractive index sensor based on an on-chip silicon nitride (Si3N4) ridge waveguide long-range surface plasmon polariton (LRSPP) is theoretically designed. The waveguide sensor consists of a gold film to enable the plasmonic resonance on top of a Cytop polymer layer. A proper finite element method was used to design and optimize the geometric parameters at the optical wavelength of 633 nm. In addition, the spectral performance was evaluated using the transfer matrix method from 580 to 680 nm. The redshifted interference spectrum results from an increasing analyte refractive index. The sensitivities of 6313 dB/cm/RIU and 251.82 nm/RIU can be obtained with a 400 nm wide and 25 nm thick Au layer. The proposed sensor has the potential for point-of-care applications considering its compactness and simplicity of construction.

2-Hydroxychalcone-ß-Cyclodextrin Conjugate with pH-Modulated Photoresponsive Binding Properties.

Stimuli-responsive supramolecular receptors are important building blocks for the construction of self-assembled functional materials. We report the design and synthesis of a pH- and light-responsive 2-hydroxychalcone-ß-cyclodextrin conjugate (1-Ct) and its characterization by spectroscopic and computational methods. 1-Ct follows the typical reaction network of trans-chalcone-flavylium photoswitches. Upon light irradiation, 1-Ct can be photochemically converted into the cis-chalcone/hemiketal forms (1-Cc/1-B) under neutral pH conditions or to the flavylium cation (1-AH+) at acidic pH values. This stimuli-responsive ß-cyclodextrin host, 1-Ct, was found to form stronger intramolecular self-inclusion complexes (Kintra = 14) than 1-AH+ (Kintra = 3) and weaker than 1-Cc/1-B (overall Kintra = 179), allowing control over their stability and binding properties by combinations of pH and light stimuli.

LC-HRMS Profiling of Paralytic Shellfish Toxins in Mytilus galloprovincialis after a Gymnodinium catenatum Bloom.

Saxitoxin and its more than 50 analogues are a group of naturally occurring neurotoxins collectively designated as paralytic shellfish toxins (PSTs). PSTs are toxic to humans and maximum legal limits in seafood have been implemented by regulatory authorities worldwide. In the European Union, monitoring of PSTs is performed using the AOAC Official Method 2005.06, based on liquid chromatography coupled with fluorescence detection (LC- FLD). However, this method has been suggested to not effectively detect the emerging C-11 hydroxyl (M-toxins) and benzoate (GC-toxins) analogues, with these analogues currently not being surveyed in monitoring programs. In this study, a liquid chromatography-high resolution mass spectrometry (LC-HRMS) method was used to search for these emerging PSTs in mussels, Mytilus galloprovincialis, contaminated following an intense Gymnodinium catenatum bloom in the Tagus estuary (Lisbon, Portugal). Five M-toxins (M1, M2, M6, dcM6, and dcM10), but no GC-toxins, were detected in the mussels' whole-soft body tissue. Moreover, the classical PSTs (C1 to C4, GTX 4 to GTX6, dcGTX1 to dcGTX4, dcSTX, dcNEO, and STX) were also found and comprised the largest fraction of the PSTs' profile. The presence of unregulated PSTs in edible mussel samples suggests potential seafood safety risks and urges further research to determine the frequency of these analogues in seafood and their contribution to toxicity.

Quantitation Overcoming Matrix Effects of Lipophilic Toxins in Mytilus galloprovincialis by Liquid Chromatography-Full Scan High Resolution Mass Spectrometry Analysis (LC-HR-MS).

The analysis of marine lipophilic toxins in shellfish products still represents a challenging task due to the complexity and diversity of the sample matrix. Liquid chromatography coupled with mass spectrometry (LC-MS) is the technique of choice for accurate quantitative measurements in complex samples. By combining unambiguous identification with the high selectivity of tandem MS, it provides the required high sensitivity and specificity. However, LC-MS is prone to matrix effects (ME) that need to be evaluated during the development and validation of methods. Furthermore, the large sample-to-sample variability, even between samples of the same species and geographic origin, needs a procedure to evaluate and control ME continuously. Here, we analyzed the toxins okadaic acid (OA), dinophysistoxins (DTX-1 and DTX-2), pectenotoxin (PTX-2), yessotoxin (YTX) and azaspiracid-1 (AZA-1). Samples were mussels (Mytilus galloprovincialis), both fresh and processed, and a toxin-free mussel reference material. We developed an accurate mass-extracted ion chromatogram (AM-XIC) based quantitation method using an Orbitrap instrument, evaluated the ME for different types and extracts of mussel samples, characterized the main compounds co-eluting with the targeted molecules and quantified toxins in samples by following a standard addition method (SAM). An AM-XIC based quantitation of lipophilic toxins in mussel samples using high resolution and accuracy full scan profiles (LC-HR-MS) is a good alternative to multi reaction monitoring (MRM) for instruments with HR capabilities. ME depend on the starting sample matrix and the sample preparation. ME are particularly strong for OA and related toxins, showing values below 50% for fresh mussel samples. Results for other toxins (AZA-1, YTX and PTX-2) are between 75% and 110%. ME in unknown matrices can be evaluated by comparing their full scan LC-HR-MS profiles with those of known samples with known ME. ME can be corrected by following SAM with AM-XIC quantitation if necessary.

High Sensitivity Surface Plasmon Resonance Sensor Based on a Ge-Doped Defect and D-Shaped Microstructured Optical Fiber.

In this work a plasmonic sensor with a D-Shaped microstructured optical fiber (MOF) is proposed to detect a wide range of analyte refractive index (RI ;na) by doping the pure silica (SiO2) core with distinct concentrations of Germanium Dioxide (GeO2), causing the presentation of high spectral sensitivity. In this case, the fiber is shaped by polishing a coating of SiO2, on the region that will be doped with GeO2, in the polished area, a thin gold (Au) layer, which constitutes the plasmonic material, is introduced, followed by the analyte, in a way which the gold layer is deposited between the SiO2. and the analyte. The numerical results obtained in the study shows that the sensor can determine efficiently a range of 0.13 refractive index units (RIU), with a limit operation where na varies from 1.32 to 1.45. Within this application, the sensor has reached an average wavelength sensitivity (WS) of up to 11,650.63 nm/RIU. With this level of sensitivity, the D-Shaped format and wide range of na detection, the proposed fiber has great potential for sensing applications in several areas.

Starch flow behavior alone and under different glidants action using the shear cell method.

The objective of this work was to analyze the flow behavior of a commonly used filler (pregelatinised starch) and the effect of two of the most used lubricants (talc and colloidal silicon dioxide). The studies were carried out according to the conventional methods (Angle of Repose, Bulk and Tapped densities and from these the Compressibility Index) and shear cell methods (Brookfield Powder Flow Tester apparatus) described in European Pharmacopeia (Ph. Eur.). The results showed some surprising and unexpected values for the flow behavior of this filler under influence of the methods and the used glidants. Regarding pure starch and mixtures containing talc, the flow behavior was similar between them and the Flow Index (ffc) values varied between 1.8 and 4 (very cohesive and cohesive) as consolidation stress (σ1) increased. In this case, the glidant effect was not observed. However, for the mixtures of starch with colloidal silicon dioxide this effect was observed providing Flow Index (ffc) values between 2.6 and 8.9 (cohesive and easy-flowing) as consolidation stress (σ1) increased. Other parameters that are also used to characterize flow properties, more specifically, within silos, chutes and hoppers, such as effective angle of internal friction (φe), effective angle of wall friction (φx), critical arching and critical rathole values, provided similar information. Based in the obtained results from all tests it can be said that the talc did not induce improvement on the starch flow behavior in the used conditions in opposition to the effect produced by colloidal silicon dioxide.HighlightsExample 1. A good flowability of powders is needed in order to be compressed/filled;Example 2. The overcome the poor flow it is usual to use glidants;Example 3. CSD improved the pregelatinised starch (Starch 1500®) flow;Example 4. Talc do not have relevant effect in the pregelatinised starch (Starch 1500®) flow;Example 5. Powder FlowTester method showed more complete and consistent results.

Competing pathways for photoremovable protecting groups: the effects of solvent, oxygen and encapsulation.

Extending the applications of Photoremovable Protecting Groups (PPGs) to "cage" phenols has generally met with unusually complex PPG byproducts. In this study, we demonstrate that the p-hydroxyphenacyl (pHP) cage for both simple and complex phenolics, including tyrosine, dispenses free phenols. With the simpler unsubstituted phenols, the reaction is governed by their Brønsted Leaving Group ability. On the other hand, the byproducts of the cage vary with these phenols. For the more acidic phenols the cage byproduct follows the Favorskii rearrangement to form p-hydroxyphenylacetic acid whereas for the weaker phenols other reactions such as reduction and hydrolysis begin to emerge. When the photolysis is conducted in octa acid (OA) containers, non-Favorskii, unrearranged fragments of the cage and other byproducts arise.

Energy Harvesting Technologies for Structural Health Monitoring of Airplane Components-A Review.

With the aim of increasing the efficiency of maintenance and fuel usage in airplanes, structural health monitoring (SHM) of critical composite structures is increasingly expected and required. The optimized usage of this concept is subject of intensive work in the framework of the EU COST Action CA18203 "Optimising Design for Inspection" (ODIN). In this context, a thorough review of a broad range of energy harvesting (EH) technologies to be potentially used as power sources for the acoustic emission and guided wave propagation sensors of the considered SHM systems, as well as for the respective data elaboration and wireless communication modules, is provided in this work. EH devices based on the usage of kinetic energy, thermal gradients, solar radiation, airflow, and other viable energy sources, proposed so far in the literature, are thus described with a critical review of the respective specific power levels, of their potential placement on airplanes, as well as the consequently necessary power management architectures. The guidelines provided for the selection of the most appropriate EH and power management technologies create the preconditions to develop a new class of autonomous sensor nodes for the in-process, non-destructive SHM of airplane components.

A Visible-Near-Infrared Light-Responsive Host-Guest Pair with Nanomolar Affinity in Water.

The discovery of stimuli-responsive high affinity host-guest pairs with potential applications under biologically relevant conditions is a challenging goal. This work reports a high-affinity 1:1 complex formed between cucurbit[8]uril and a water-soluble photochromic diarylethene derivative. It was found that, by confining the open isomer within the cavity of the receptor, a redshift in the absorption spectrum and an enhancement of the photocyclization quantum yield from Φ=0.04 to Φ=0.32 were induced. This improvement in the photochemical performance enables quantitative photocyclization with visible light that, together with the near-infrared light-induced ring-opening reaction and the 100-fold selectivity for the closed isomer, confirms this as an outstanding light-responsive affinity pair.

Supramolecular photochemistry of encapsulated caged ortho-nitrobenzyl triggers.

ortho-Nitrobenzyl (oNB) triggers have been extensively used to release various molecules of interest. However, the toxicity and reactivity of the spent chromophore, o-nitrosobenzaldehyde, remains an unaddressed difficulty. In this study we have applied the well-established supramolecular photochemical concepts to retain the spent trigger o-nitrosobenzaldehyde within the organic capsule after release of water-soluble acids and alcohols. The sequestering power of organic capsules for spent chromophores during photorelease from ortho-nitrobenzyl esters, ethers and alcohols is demonstrated with several examples.

Multifactorial explanatory model of depression in patients with rheumatoid arthritis: a structural equation approach.

OBJECTIVES: Depressive symptoms are common among patients with rheumatoid arthritis (RA). This study was aimed at developing a multifactorial explanatory model that evaluated the influence of personality traits, disease activity, perceived disease impact, and comorbidities. METHODS: This cross-sectional study used structural equation modelling estimation to analyse the associations between these dimensions, pursuing three hypotheses. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale, disease impact by the Rheumatoid Arthritis Impact of Disease score, personality by the Ten Item Personality Inventory and the disease activity through the Disease Activity Score 28 joints. The influence of comorbidities was investigated by multigroup analysis. RESULTS: The final model derived from data of 254 patients presented a good fit. Disease activity had an indirect relation with depressive symptoms mediated by disease impact (ß=0.17, p<0.001), but the direct relationship between disease activity and depressive symptoms was not significant (ß=0.09; p=0.07). "Positive" personality had a strong negative direct relation with depressive symptoms as well as an indirect relationship mediated by disease impact (total effect ß=-0.61, p<0.001). The final proposed model explained 58% of the variance of depressive symptoms. Multigroup analysis showed an invariant model when comparing patients with and without comorbidities (dχ2=9.03; df=12; p=0.70). CONCLUSIONS: Personality characteristics seem to have a major influence upon the impact of disease and the patient's adjustment to RA, including the vulnerability or resilience to depression. Individual personality traits deserve attention in tailored assessment and treatment of patients with RA, in order to optimise outcomes.

The long non-coding RNA FMR4 promotes proliferation of human neural precursor cells and epigenetic regulation of gene expression in trans.

Triplet repeat expansions in the Fragile X mental retardation 1 (FMR1) gene cause either intellectual disability and autism, or adult-onset neurodegeneration, with poorly understood variability in presentation. Previous studies have identified several long noncoding RNAs (lncRNAs) at the FMR1 locus, including FMR4. Similarly to FMR1, FMR4 is silenced by large-repeat expansions that result in enrichment of DNA and histone methylation within the shared promoter and repeat sequence, suggesting a possible role for this noncoding RNA in the pathophysiology of Fragile X. We therefore assessed the functional role of FMR4 to gain further insight into the molecular processes in Fragile X-associated disorders. Previous work showed that FMR4 does not exhibit cis-regulation of FMR1. Here, we found that FMR4 is a chromatin-associated transcript and, using genome-wide chromatin immunoprecipitation experiments, showed that FMR4 alters the chromatin state and the expression of several hundred genes in trans. Among the genes regulated by FMR4, we found enrichment for those involved in neural development and cellular proliferation. S-phase marker assays further demonstrated that FMR4 may promote cellular proliferation, rather than differentiation, of human neural precursor cells (hNPCs). By establishing this novel function for FMR4 in hNPCs, we lend support to existing evidence of the epigenetic involvement of lncRNA in nervous system development, and increase our understanding of the complex pathogenesis underlying neurological disorders associated with FMR1 repeat expansions.

Quantitative analysis of biogenic polyamines in distilled drinks by direct electrospray ionization tandem mass spectrometry using a nanocontainer.

RATIONALE: Biogenic polyamines in drinks have been implicated in undesirable physiological effects. Methods for their detection and quantification usually involve derivatization, pre-concentration and clean-up. To assist the evaluation of the potential risk of distillates, it was important to develop a simple and fast analytical method, which is described in this study. METHODS: Biogenic polyamines were selectively encapsulated after addition of a nanocontainer, cucurbit[7]uril (50 µM), to the distilled drink samples, which were acidified with HCl (pH 3) prior addition of the nanocontainer. The quantification of polyamines was achieved by direct infusion electrospray ionization quadrupole ion trap mass spectrometry in the multiple reaction monitoring mode, using encapsulated amantadine as internal standard, and by monitoring signals originating from their host-guest complexes. RESULTS: Six point calibration curves, ranging from 0.5 µM to 20 µM of polyamines in water and ethanol/water (50:50), were used to establish instrument response. The method was validated by analysis of fortified Arbutus spirits. Samples of Arbutus and grape pomace spirits were also analyzed. Linear responses were observed for all polyamines and were similar in water, hydro-alcoholic solutions and fortified Arbutus spirits. Putrescine the simple polyamine was detected only in grape pomace distillate samples. CONCLUSIONS: A quantitative method was developed for rapid and simple analysis of biogenic polyamines in distilled drinks. The detection limits depend on the ionization properties of the samples. Encapsulated amantadine can be used to probe these properties and method application. Copyright © 2016 John Wiley & Sons, Ltd.

Regulation of adaptive behaviour during fasting by hypothalamic Foxa2.

The lateral hypothalamic area is considered the classic 'feeding centre', regulating food intake, arousal and motivated behaviour through the actions of orexin and melanin-concentrating hormone (MCH). These neuropeptides are inhibited in response to feeding-related signals and are released during fasting. However, the molecular mechanisms that regulate and integrate these signals remain poorly understood. Here we show that the forkhead box transcription factor Foxa2, a downstream target of insulin signalling, regulates the expression of orexin and MCH. During fasting, Foxa2 binds to MCH and orexin promoters and stimulates their expression. In fed and in hyperinsulinemic obese mice, insulin signalling leads to nuclear exclusion of Foxa2 and reduced expression of MCH and orexin. Constitutive activation of Foxa2 in the brain (Nes-Cre/+;Foxa2T156A(flox/flox) genotype) results in increased neuronal MCH and orexin expression and increased food consumption, metabolism and insulin sensitivity. Spontaneous physical activity of these animals in the fed state is significantly increased and is similar to that in fasted mice. Conditional activation of Foxa2 through the T156A mutation expression in the brain of obese mice also resulted in improved glucose homeostasis, decreased fat and increased lean body mass. Our results demonstrate that Foxa2 can act as a metabolic sensor in neurons of the lateral hypothalamic area to integrate metabolic signals, adaptive behaviour and physiological responses.