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The hypometabolism induced by fasting has great potential in maintaining health and improving survival in extreme environments, among which thyroid hormone (TH) plays an important role in the adaptation and the formation of new energy metabolism homeostasis during long-term fasting. In the present review, we emphasize the potential of long-term fasting to improve physical health and emergency rescue in extreme environments, introduce the concept and pattern of fasting and its impact on the body’s energy metabolism consumption. Prolonged fasting has more application potential in emergency rescue in special environments. The changes of THs caused by fasting, including serum biochemical characteristics, responsiveness of the peripheral and central hypothalamus-pituitary-thyroid (HPT) axis, and differential changes of TH metabolism, are emphasized in particular. It was proposed that the variability between brain and liver tissues in THs uptake, deiodination activation and inactivation is the key regulatory mechanism for the cause of peripheral THs decline and central homeostasis. While hypothalamic tanycytes play a pivotal role in the fine regulation of the HPT negative feedback regulation during long-term fasting. The study progress of tanycytes on thyrotropin-releasing hormone (TRH) release and deiodination is described in detail. In conclusion, the combination of the decrease of TH metabolism in peripheral tissues and stability in the central HPT axis maintains the basal physiological requirement and new energy metabolism homeostasis to adapt to long-term food scarcity. The molecular mechanisms of this localized and differential regulation will be a key research direction for developing measures for hypometabolic applications in extreme environment. [ABSTRACT FROM AUTHOR]

2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid (EC), acting as a full agonist at both CB1 and CB2 cannabinoid receptors. It is synthesized on demand in postsynaptic membranes through the sequential action of phosphoinositide-specific phospholipase Cβ1 (PLCβ1) and diacylglycerol lipase α (DAGLα), contributing to retrograde signaling upon interaction with presynaptic CB1. However, 2-AG production might also involve various combinations of PLC and DAGL isoforms, as well as additional intracellular pathways implying other enzymes and substrates. Three other alternative pathways of 2-AG synthesis rest on the extracellular cleavage of 2-arachidonoyl-lysophospholipids by three different hydrolases: glycerophosphodiesterase 3 (GDE3), lipid phosphate phosphatases (LPPs), and two members of ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPP6–7). We propose the names of AlterAG-1, -2, and -3 for three pathways sharing an ectocellular localization, allowing them to convert extracellular lysophospholipid mediators into 2-AG, thus inducing typical signaling switches between various G-protein-coupled receptors (GPCRs). This implies the critical importance of the regioisomerism of both lysophospholipid (LPLs) and 2-AG, which is the object of deep analysis within this review. The precise functional roles of AlterAGs are still poorly understood and will require gene invalidation approaches, knowing that both 2-AG and its related lysophospholipids are involved in numerous aspects of physiology and pathology, including cancer, inflammation, immune defenses, obesity, bone development, neurodegeneration, or psychiatric disorders. [ABSTRACT FROM AUTHOR]

Neurons in the caudal nucleus of the solitary tract (cNTS) and intermediate reticular nucleus (IRt) that express the glucagon gene (Gcg) give rise to glucagon-like peptide 1 (GLP1)-immunopositive axons in the spinal cord and many subcortical brain regions. Central GLP1 receptor signaling contributes to motivated behavior and stress responses in rats and mice, in which hindbrain GLP1 neurons are activated to express c-Fos in a metabolic state-dependent manner. The present study examined whether GLP1 inputs to distinct brain regions arise from distinct subsets of Gcg-expressing neurons, and mapped the distribution of axon collaterals arising from projection-defined GLP1 neural populations. Using our Gcg-Cre knock-in rat model, Cre-dependent adeno-associated virus (AAV) tracing was conducted in adult male and female rats to compare axonal projections of IRt versus cNTS GLP1 neurons. Overlapping projections were observed in all brain regions that receive GLP1 input, with the caveat that cNTS injections produced Cre-dependent labeling of some IRt neurons, and vice versa. In additional experiments, specific diencephalic or limbic forebrain nuclei were microinjected with Cre-dependent retrograde AAVs (AAVrg) that expressed reporters to fully label the axon collaterals of transduced GLP1 neurons. AAVrg injected into each forebrain site labeled Gcg-expressing neurons in both the cNTS and IRt. The collective axon collaterals of labeled neurons entered the spinal cord and every brain region previously reported to contain GLP1-positive axons. These results indicate that the axons of GLP1 neural populations that innervate the thalamic paraventricular nucleus, paraventricular nucleus of the hypothalamus, and/or bed nucleus of the stria terminalis collectively innervate all central regions that receive GLP1 axonal input. [ABSTRACT FROM AUTHOR]

The European Commission asked EFSA to update its 2011 risk assessment on tetrabromobisphenol A (TBBPA) and five derivatives in food. Neurotoxicity and carcinogenicity were considered as the critical effects of TBBPA in rodent studies. The available evidence indicates that the carcinogenicity of TBBPA occurs via non‐genotoxic mechanisms. Taking into account the new data, the CONTAM Panel considered it appropriate to set a tolerable daily intake (TDI). Based on decreased interest in social interaction in male mice, a lowest observed adverse effect level (LOAEL) of 0.2 mg/kg body weight (bw) per day was identified and selected as the reference point for the risk characterisation. Applying the default uncertainty factor of 100 for inter‐ and intraspecies variability, and a factor of 3 to extrapolate from the LOAEL to NOAEL, a TDI for TBBPA of 0.7 μg/kg bw per day was established. Around 2100 analytical results for TBBPA in food were used to estimate dietary exposure for the European population. The most important contributors to the chronic dietary LB exposure to TBBPA were fish and seafood, meat and meat products and milk and dairy products. The exposure estimates to TBBPA were all below the TDI, including those estimated for breastfed and formula‐fed infants. Accounting for the uncertainties affecting the assessment, the CONTAM Panel concluded with 90%–95% certainty that the current dietary exposure to TBBPA does not raise a health concern for any of the population groups considered. There were insufficient data on the toxicity of any of the TBBPA derivatives to derive reference points, or to allow a comparison with TBBPA that would support assignment to an assessment group for the purposes of combined risk assessment. [ABSTRACT FROM AUTHOR]

Background: The Thr92Ala-DIO2 polymorphism has been associated with clinical outcomes in hospitalized patients with COVID-19 and neuropsychiatric diseases. This study examines the impact of the Thr92Ala-DIO2 polymorphism on neuropsychological symptoms, particularly depressive symptoms, in patients who have had moderate to severe SARS-CoV-2 infection and were later discharged. Methods: Our prospective cohort study, conducted from June to August 2020, collected data from 273 patients hospitalized with COVID-19. This included thyroid function tests, inflammatory markers, hematologic indices, and genotyping of the Thr92Ala-DIO2 polymorphism. Post-discharge, we followed up with 68 patients over 30 to 45 days, dividing them into depressive (29 patients) and non-depressive (39 patients) groups based on their Beck Depression Inventory scores. Results: We categorized 68 patients into three groups based on their genotypes: Thr/Thr (22 patients), Thr/Ala (41 patients), and Ala/Ala (5 patients). Depressive symptoms were less frequent in the Thr/Ala group (29.3%) compared to the Thr/Thr (59.1%) and Ala/Ala (60%) groups (p = 0.048). The Thr/Ala heterozygous genotype correlated with a lower risk of post-COVID-19 depression, as shown by univariate and multivariate logistic regression analyses. These analyses, adjusted for various factors, indicated a 70% to 81% reduction in risk. Conclusion: Our findings appear to be the first to show that heterozygosity for Thr92Ala-DIO2 in patients with COVID-19 may protect against post-COVID-19 depression symptoms up to 2 months after the illness. [ABSTRACT FROM AUTHOR]

Unacylated ghrelin (UAG), the unacylated form of ghrelin, accounts for 80%–90% of its circulation. Accumulated studies have pointed out that UAG may be used to treat metabolic disorders. This study aimed to investigate the effect of intestinal perfusion of UAG on metabolically associated fatty liver disease (MAFLD) induced by a high-fat diet and its possible mechanisms. Neuronal retrograde tracking combined with immunofluorescence, central administration of a glucagon-like peptide-1 receptor (GLP-1R) antagonist, and hepatic vagotomy was performed to reveal its possible mechanism involving a central glucagon-like peptide-1 (GLP-1) pathway. The results showed that intestinal perfusion of UAG significantly reduced serum lipids, aminotransferases, and food intake in MAFLD rats. Steatosis and lipid accumulation in the liver were significantly alleviated, and lipid metabolism-related enzymes in the liver were regulated. UAG upregulated the expression of GLP-1 receptor (GLP-1R) in the paraventricular nucleus (PVN) and GLP-1 in the nucleus tractus solitarii (NTS), as well as activated GLP-1 neurons in the NTS. Furthermore, GLP-1 fibers projected from NTS to PVN were activated by the intestinal perfusion of UAG. However, hepatic vagotomy and GLP-1R antagonists delivered into PVN before intestinal perfusion of UAG partially attenuated its alleviation of MAFLD. In conclusion, intestinal perfusion of UAG showed a therapeutic effect on MAFLD, which might be related to its activation of the GLP-1 neuronal pathway from NTS to PVN. The present results provide a new strategy for the treatment of MAFLD. NEW & NOTEWORTHY: Intestinal perfusion of UAG, the unacylated form of ghrelin, has shown promising potential for treating MAFLD. This study unveils a potential mechanism involving the central GLP-1 pathway, with UAG upregulating GLP-1R expression and activating GLP-1 neurons in specific brain regions. These findings propose a novel therapeutic strategy for MAFLD treatment through UAG and its modulation of the GLP-1 neuronal pathway. [ABSTRACT FROM AUTHOR]

Introduction: Mutations and single nucleotide polymorphisms (SNPs) in the genes encoding the network of proteins involved in thyroid hormone signaling (TH) may have implications for the effectiveness of the treatment of hypothyroidism with LT4. It is conceivable that loss-of-function mutations or SNPs impair the ability of LT4 to be activated to T3, reach its targets, and ultimately resolve symptoms of hypothyroidism. Some of these patients do benefit from therapy containing LT4 and LT3. Methods: Here, we reviewed the PubMed and examined gene mutations and SNPs in the TH cellular transporters, deiodinases, and TH receptors, along with their impact on TH signaling, and potential clinical implications. Results: In some mechanisms, such as the Thr92Ala-DIO2 SNP, there is a compelling rationale for reduced T4 to T3 activation that limits the effectiveness of LT4 to restore euthyroidism. In other mechanisms, a potential case can be made but more studies with a larger number of individuals are needed. Discussion/Conclusion: Understanding the clinical impact of the genetic makeup of LT4-treated patients may help in the preemptive identification of those individuals that would benefit from therapy containing LT3. [ABSTRACT FROM AUTHOR]

The commercial introduction of a novel electronic device is often preceded by a lengthy material optimization phase devoted to the suppression of device noise as much as possible. The emergence of novel computing architectures, however, triggers a paradigm shift in noise engineering, demonstrating that non-suppressed but properly tailored noise can be harvested as a computational resource in probabilistic computing schemes. Such a strategy was recently realized on the hardware level in memristive Hopfield neural networks, delivering fast and highly energy efficient optimization performance. Inspired by these achievements, we perform a thorough analysis of simulated memristive Hopfield neural networks relying on realistic noise characteristics acquired on various memristive devices. These characteristics highlight the possibility of orders of magnitude variations in the noise level depending on the material choice as well as on the resistance state (and the corresponding active region volume) of the devices. Our simulations separate the effects of various device non-idealities on the operation of the Hopfield neural network by investigating the role of the programming accuracy as well as the noise-type and noise amplitude of the ON and OFF states. Relying on these results, we propose optimized noise tailoring and noise annealing strategies, comparing the impact of internal noise to the effect of external perturbation injection schemes. [ABSTRACT FROM AUTHOR]

Simple Summary: Normal feed intake and efficient nutrient absorption are prerequisites for achieving rapid growth, high body weight and dimensions, high carcass and meat yield, and feed efficiency in chickens. Gut hormones released from enteroendocrine cells (EECs) have been recognized as regulators for appetite as well as nutrient absorption in other species. However, the underlying regulation mechanisms of appetite control and nutrient absorption by gut hormones are not fully understood in chickens. This review suggests that gut hormones released from EECs play important roles in appetite and nutrient absorption, and these hormones are considered to be able to influence the reduction of feed intake by infection (e.g., Eimeria spp. and Salmonella spp.) and environmental stresses (e.g., heat stress and high stock density). This review focuses on the role of hormones derived from enteroendocrine cells (EECs) on appetite and nutrient absorption in chickens. In response to nutrient intake, EECs release hormones that act on many organs and body systems, including the brain, gallbladder, and pancreas. Gut hormones released from EECs play a critical role in the regulation of feed intake and the absorption of nutrients such as glucose, protein, and fat following feed ingestion. We could hypothesize that EECs are essential for the regulation of appetite and nutrient absorption because the malfunction of EECs causes severe diarrhea and digestion problems. The importance of EEC hormones has been recognized, and many studies have been carried out to elucidate their mechanisms for many years in other species. However, there is a lack of research on the regulation of appetite and nutrient absorption by EEC hormones in chickens. This review suggests the potential significance of EEC hormones on growth and health in chickens under stress conditions induced by diseases and high temperature, etc., by providing in-depth knowledge of EEC hormones and mechanisms on how these hormones regulate appetite and nutrient absorption in other species. [ABSTRACT FROM AUTHOR]

Background: Thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) have been identified as direct regulators of thyrotropin (TSH) and thyroid hormone (TH) levels. They play a significant role in context of negative feedback by TH at the level of TRH gene expression and during fasting when TH levels fall due, in part, to suppression of TRH gene expression. Methods: To test these functions directly for the first time, we used a chemogenetic approach and activated PVN TRH neurons in both fed and fasted mice. Next, to demonstrate the signals that regulate the fasting response in TRH neurons, we activated or inhibited agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons in the arcuate nucleus of the hypothalamus of fed or fasted mice, respectively. To determine if the same TRH neurons responsive to melanocortin signaling mediate negative feedback by TH, we disrupted the thyroid hormone receptor beta (TRβ) in all melanocortin 4 receptor (MC4R) neurons in the PVN. Results: Activation of TRH neurons led to increased TSH and TH levels within 2 hours demonstrating the specific role of PVN TRH neurons in the regulation of the hypothalamic–pituitary–thyroid (HPT) axis. Moreover, activation of PVN TRH neurons prevented the fall in TH levels in fasting mice. Stimulation of AgRP/NPY neurons led to a fall in TH levels despite increasing feeding. Inhibition of these same neurons prevented the fall in TH levels during a fast presumably via their ability to directly regulate PVN TRH neurons via, in part, the MC4R. Surprisingly, TH-mediated feedback was not impaired in mice lacking TRβ in MC4R neurons. Conclusions: TRH neurons are major regulators of the HPT axis and the fasting-induced suppression of TH levels. The latter relies, at least in part, on the activation of AgRP/NPY neurons in the arcuate nucleus. Interestingly, present data do not support an important role for TRβ signaling in regulating MC4R neurons in the PVN. Thus, it remains possible that different subsets of TRH neurons in the PVN mediate responses to energy balance and to TH feedback. [ABSTRACT FROM AUTHOR]

Resistive memories are outstanding electron devices that have displayed a large potential in a plethora of applications such as nonvolatile data storage, neuromorphic computing, hardware cryptography, etc. Their fabrication control and performance have been notably improved in the last few years to cope with the requirements of massive industrial production. However, the most important hurdle to progress in their development is the so‐called cycle‐to‐cycle variability, which is inherently rooted in the resistive switching mechanism behind the operational principle of these devices. In order to achieve the whole picture, variability must be assessed from different viewpoints going from the experimental characterization to the adequation of modeling and simulation techniques. Herein, special emphasis is put on the modeling part because the accurate representation of the phenomenon is critical for circuit designers. In this respect, a number of approaches are used to the date: stochastic, behavioral, mesoscopic..., each of them covering particular aspects of the electron and ion transport mechanisms occurring within the switching material. These subjects are dealt with in this review, with the aim of presenting the most recent advancements in the treatment of variability in resistive memories. [ABSTRACT FROM AUTHOR]

The resistance state of filamentary memristors can be tuned by relocating only a few atoms at interatomic distances in the active region of a conducting filament. Thereby the technology holds promise not only in its ultimate downscaling potential and energy efficiency but also in unprecedented speed. Yet, the breakthrough in high‐frequency applications still requires the clarification of the dominant mechanisms and inherent limitations of ultra‐fast resistive switching. Here bipolar, multilevel resistive switchings are investigated in tantalum pentoxide based memristors with picosecond time resolution. Cyclic resistive switching operation due to 20 ps long voltage pulses of alternating polarity are experimentally demonstrated. The analysis of the real‐time response of the memristor reveals that the set switching can take place at the picosecond time‐scale where it is only compromised by the bandwidth limitations of the experimental setup. In contrast, the completion of the reset transitions significantly exceeds the duration of the ultra‐short voltage bias, demonstrating the dominant role of thermal diffusion and underlining the importance of dedicated thermal engineering for future high‐frequency memristor circuit applications. [ABSTRACT FROM AUTHOR]

The discovery of leptin in 1994 was an "eureka moment" in the field of neurometabolism that provided new opportunities to better understand the central control of energy balance and glucose metabolism. Rapidly, a prevalent model in the field emerged that pro‐opiomelanocortin (POMC) neurons were key in promoting leptin's anorexigenic effects and that the arcuate nucleus of the hypothalamus (ARC) was a key region for the regulation of energy homeostasis. While this model inspired many important discoveries, a growing body of literature indicates that this model is now outdated. In this review, we re‐evaluate the hypothalamic leptin–melanocortin model in light of recent advances that directly tackle previous assumptions, with a particular focus on the ARC. We discuss how segregated and heterogeneous these neurons are, and examine how the development of modern approaches allowing spatiotemporal, intersectional, and chemogenetic manipulations of melanocortin neurons has allowed a better definition of the complexity of the leptin–melanocortin system. We review the importance of leptin in regulating glucose homeostasis, but not food intake, through direct actions on ARC POMC neurons. We further highlight how non‐POMC, GABAergic neurons mediate leptin's direct effects on energy balance and influence POMC neurons. [ABSTRACT FROM AUTHOR]

Introduction: Emerging evidence has shown that the glucagon-like peptide-1 (GLP-1) agonist can be used to treat Alzheimer disease; however, knowledge of its neural targets is limited. To understand the neural substrates of GLP-1, we have done whole brain mapping for GLP-1 and its receptor (GLP-1R), in 30 human brains. Methods: GLP-1 expression was studied by immuno-histochemistry and confirmed by the western blot method. The GLP-1R gene expression was studied by reverse transcription polymerase chain reaction. Results: GLP-1 expression was observed in most of the cortical areas (maximum in frontal, prefrontal and parietal cortex), diencephalon, and brainstem, but not in the cerebellum. Protein expression studies validated these results. The highest expression of GLP-1R was found in the frontal cortex. The orbitofrontal cortex and cerebellum had negligible expression. Hippocampus demonstrated a significant presence of GLP-1R but patchy immunoreactivity to GLP-1. GLP-1R presence in most of the human cortical regions and absence in the cerebellum is the major deviation from the animal brain. Sites that might be of interest in Alzheimer have been identified. GLP-1 demonstrated an age-related decline in most of the areas after the fifth decade. At 60 years, GLP-1 was not found in any of the cortical areas except in the prefrontal cortex; however, it was present in the sub-cortical areas. Conclusion: Age-related profiling of GLP-1 in various brain areas has been analyzed, which can have an important bearing on understanding Alzheimer disease. This study provides a detailed description of GLP-1 and an brain mapping for the first time and may lead to novel treatment options targeting the GLP-1 receptors. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated fatty liver disease (MAFLD) has gained worldwide attention as a public health problem. Nonetheless, lack of enough mechanistic knowledge restrains effective treatments. It is known that thyroid hormone triiodothyronine (T3) regulates hepatic lipid metabolism, and mitochondrial function. Liver dysfunction of type 3 deiodinase (D3) contributes to MAFLD, but its role is not fully understood. Objective: To evaluate the role of D3 in the progression of MAFLD in an animal model. Methodology: Male/adult Sprague Dawley rats (n = 20) were allocated to a control group (2.93 kcal/g) and high-fat diet group (4.3 kcal/g). Euthanasia took place on the 28th week. D3 activity and expression, Uncoupling Protein 2 (UCP2) and type 1 deiodinase (D1) expression, oxidative stress status, mitochondrial, Krebs cycle and endoplasmic reticulum homeostasis in liver tissue were measured. Results: We observed an increase in D3 activity/expression (p < 0.001) related to increased thiobarbituric acid reactive substances (TBARS) and carbonyls and diminished reduced glutathione (GSH) in the MAFLD group (p < 0.05). There was a D3-dependent decrease in UCP2 expression (p = 0.01), mitochondrial capacity, respiratory activity with increased endoplasmic reticulum stress in the MAFLD group (p < 0.001). Surprisingly, in an environment with lower T3 levels due to high D3 activity, we observed an augmented alpha-ketoglutarate dehydrogenase (KGDH) and glutamate dehydrogenase (GDH) enzymes activity (p < 0.05). Conclusion: Induced D3, triggered by changes in the REDOX state, decreases T3 availability and hepatic mitochondrial capacity. The Krebs cycle enzymes were altered as well as endoplasmic reticulum stress. Taken together, these results shed new light on the role of D3 metabolism in MAFLD. [ABSTRACT FROM AUTHOR]

Thyroid hormone (TH) signaling is a prerequisite of normal tissue function. Environmental pollutants with the potential to disrupt endocrine functions represent an emerging threat to human health and agricultural production. We used our Thyroid Hormone Action Indicator (THAI) mouse model to study the effects of tetrabromobisphenol A (TBBPA; 150 mg/bwkg/day orally for 6 days) and diclazuril (10.0 mg/bwkg/day orally for 5 days), a known and a potential hormone disruptor, respectively, on local TH economy. Tissue-specific changes of TH action were assessed in 90-day-old THAI mice by measuring the expression of a TH-responsive luciferase reporter in tissue samples and by in vivo imaging (14-day-long treatment accompanied with imaging on day 7, 14 and 21 from the first day of treatment) in live THAI mice. This was followed by promoter assays to elucidate the mechanism of the observed effects. TBBPA and diclazuril impacted TH action differently and tissue-specifically. TBBPA disrupted TH signaling in the bone and small intestine and impaired the global TH economy by decreasing the circulating free T4 levels. In the promoter assays, TBBPA showed a direct stimulatory effect on the hdio3 promoter, indicating a potential mechanism for silencing TH action. In contrast, diclazuril acted as a stimulator of TH action in the liver, skeletal muscle and brown adipose tissue without affecting the Hypothalamo-Pituitary-Thyroid axis. Our data demonstrate distinct and tissue-specific effects of TBBPA and diclazuril on local TH action and prove that the THAI mouse is a novel mammalian model to identify TH disruptors and their tissue-specific effects. [ABSTRACT FROM AUTHOR]

The clinical availability of tissue-specific biomarkers of thyroid hormone (TH) action constitutes a "holy grail" for the field. Scientists have investigated several TH-dependent markers, including the tissue content of triiodothyronine (T3)- the active form of TH. The study of animal models and humans indicates that the T3 content varies among different tissues, mostly due to the presence of low-affinity, high-capacity cytoplasmic T3 binding proteins. Nonetheless, given that T3 levels in the plasma and tissues are in equilibrium, T3 signaling is defined by the intracellular free T3 levels. The available techniques to assess tissue T3 are invasive and not clinically applicable. However, the tracer kinetic studies revealed that serum T3 levels can accurately predict tissue T3 content and T3 signaling in most tissues, except for the brain and pituitary gland. This is true not only for normal individuals but also for patients with hypo or hyperthyroidism-but not for patients with non-thyroidal illness syndrome. Given this direct relationship between serum and tissue T3 contents and T3 signaling in most tissues, clinicians managing patients with hypothyroidism could refocus attention on monitoring serum T3 levels. Future clinical trials should aim at correlating clinical outcomes with serum T3 levels. [ABSTRACT FROM AUTHOR]

Neuroendocrine, behavioural and autonomic responses to stressful stimuli are orchestrated by complex neural circuits. The caudal nucleus of the solitary tract (cNTS) in the dorsomedial hindbrain is uniquely positioned to integrate signals of both interoceptive and psychogenic stress. Within the cNTS, glucagon‐like peptide‐1 (GLP‐1) and prolactin‐releasing peptide (PrRP) neurons play crucial roles in organising neural responses to a broad range of stressors. In this review we discuss the anatomical and functional overlap between PrRP and GLP‐1 neurons. We outline their co‐activation in response to stressful stimuli and their importance as mediators of behavioural and physiological stress responses. Finally, we review evidence that PrRP neurons are downstream of GLP‐1 neurons and outline unexplored areas of the research field. Based on the current state‐of‐knowledge, PrRP and GLP‐1 neurons may be compelling targets in the treatment of stress‐related disorders. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a multifactorial disorder, and there is strong evidence that mitochondria play an essential role in the disorder. Factors that regulate the mechanism of the mitochondrial quality control system have been drawing more and more attention. PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α) is a powerful transcription factor involved in regulation of mitochondrial function. Glucagon-like peptide 1 (GLP-1), a brain-gut peptide, can enter the central nervous system through the blood–brain barrier and play neuroprotective role. However, whether the GLP-1R agonist liraglutide regulates mitochondrial quality control system through PGC-1α is still unclear. We administered different doses of liraglutide to intervene MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD model, and then immunofluorescence, Western blot, and stereotactic injection of lentivirus to downregulate PGC-1α were used to explore the mechanisms underlying the protective effect of liraglutide in PD. The results showed that MPTP lead to decreased mitochondrial biogenesis, disrupted mitochondrial dynamics, inhibited mitochondrial autophagy, and promoted cell apoptosis. While liraglutide effectively attenuated the neurotoxicity of MPTP, including reversing the dyskinesia caused by MPTP and preserving the expression of GLP-1R, TH, and PGC-1α in the substantia nigra (SN), further experiments showed that downregulation of PGC-1α expression via stereotactic injection PGC-1α lentivirus into the SN reversed the liraglutide protective effects. By PGC-1α downregulation, we found that PGC-1α can not only regulate mitochondria biogenesis, mitochondria dynamics, and autophagy, but also regulate cell apoptosis. In summary, liraglutide has a neuroprotective effect in the PD model induced by MPTP. This protective effect is accomplished by activating PGC-1α, which regulates the mitochondrial quality control system. [ABSTRACT FROM AUTHOR]

The glucagon-like peptide-1 (GLP-1) plays important roles in the regulation of food intake and energy metabolism. Peripheral or central GLP-1 suppresses food intake and reduces body weight. The electrophysiological properties of neurons in the mammalian central nervous system reflect the neuronal excitability and the functional organization of the brain. Recent studies focus on elucidating GLP-1-induced suppression of feeding behaviors and modulation of neuronal electrophysiological properties in several brain regions. Here, we summarize that activation of GLP-1 receptor (GLP-1R) suppresses food intake and induces postsynaptic depolarization of membrane potential and/or presynaptic modulation of glutamatergic or GABAergic neurotransmission in brain nuclei located within the medulla oblongata, pons, mesencephalon, diencephalon, and telencephalon. This review may provide a background to guide future research about the cellular mechanisms of GLP-1-induced feeding inhibition. [ABSTRACT FROM AUTHOR]

Neuromorphic in‐memory computing systems, comprising artificial synapses and neurons, can overcome the energy inefficiency and throughput limitation of today's von Neumann computing architecture. Recently, powered by the unique properties of quantum materials, for example, high mobility, outstanding sensitivity, and strong quantum effect, researchers have built quantum artificial synapses to mimic the biological ones. These quantum electronic/photonic synapses can precisely define their conductance state (or synaptic weight) for emulating synaptic behaviors, which shows bionic performance unreachable by other conventional materials. In this review, the significant achievements in quantum artificial synapses are summarized. First, potential quantum materials used in artificial synapses are discussed with particular attention to quantum dots, nanowires, layered materials, and quasi‐2DEG interfaces. Then, the major quantum effects that are utilized in quantum artificial synapses, for example, Josephson effect, quantum tunneling, and spin memory, are reviewed. In addition to the discussion on a single synaptic device, the macroscale integration into artificial visual systems and artificial nerve networks are also highlighted. Finally, the associated future research trends and target applications are also discussed. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) exerts its anorexigenic effect at least partly via the proopiomelanocortin (POMC) neurons of the arcuate (ARC) nucleus. These neurons are known to express GLP-1 receptor (GLP-1R). The aim of the study was to determine whether in addition to its direct effect, GLP-1 also modulates how neuronal inputs can regulate the POMC neurons by acting on presynaptic terminals, ultrastructural and electrophysiological studies were performed on tissues of adult male mice. GLP-1R-immunoreactivity was associated with the cell membrane of POMC neurons and with axon terminals forming synapses on these cells. The GLP-1 analog exendin 4 (Ex4) markedly increased the firing rate of all examined POMC neurons and depolarized these cells. These effects of Ex4 were prevented by intracellular administration of the G-protein blocker guanosine 5′-[β-thio]diphosphate trilithium salt (GDP-β-S). Ex4 also influenced the miniature postsynaptic currents (mPSCs) and evoked PSCs of POMC neurons. Ex4 increased the frequency of miniature excitatory PSCs (EPSCs) and the amplitude of the evoked EPSCs in half of the POMC neurons. Ex4 increased the frequency of miniature inhibitory PSCs (IPSCs) and the amplitudes of the evoked IPSCs in one-third of neurons. These effects of Ex4 were not influenced by intracellular GDP-β-S, indicating that GLP-1 signaling directly stimulates a population of axon terminals innervating the POMC neurons. The different Ex4 responsiveness of their mPSCs indicates the heterogeneity of the POMC neurons of the ARC. In summary, our data demonstrate that in addition to its direct excitatory effect on the POMC neurons, GLP-1 signaling also facilitates the presynaptic input of these cells by acting on presynaptically localized GLP-1R. [ABSTRACT FROM AUTHOR]

Background: Central sensitization is considered a critical pathogenic mechanism of chronic migraine (CM). Activation of microglia in the trigeminal nucleus caudalis (TNC) contributes to this progression. Microglial glucagon-like peptide-1 receptor (GLP-1R) activation can alleviate pain; however, whether it is involved in the mechanism of CM has not been determined. Thus, this study aims to investigate the precise role of GLP-1R in the central sensitization of CM. Methods: Repeated nitroglycerin injection-treated mice were used as a CM animal model in the experiment. To identify the distribution and cell localization of GLP-1R in the TNC, we performed immunofluorescence staining. Changes in the expression of GLP-1R, Iba-1, PI3K and p-Akt in the TNC were examined by western blotting. To confirm the effect of GLP-1R and PI3K/Akt in CM, a GLP-1R selective agonist (liraglutide) and antagonist (exendin(9–39)) and a PI3K selective antagonist (LY294002) were administered. Mechanical hypersensitivity was measured through von Frey filaments. To investigate the role of GLP-1R in central sensitization, calcitonin gene-related peptide (CGRP) and c-fos were determined using western blotting and immunofluorescence. To determine the changes in microglial activation, IL-1β and TNF-α were examined by western blotting, and the number and morphology of microglia were measured by immunofluorescence. We also confirmed the effect of GLP-1R on microglial activation in lipopolysaccharide-treated BV-2 microglia. Results: The protein expression of GLP-1R was increased in the TNC after nitroglycerin injection. GLP-1R was colocalized with microglia and astrocytes in the TNC and was fully expressed in BV-2 microglia. The GLP-1R agonist liraglutide alleviated basal allodynia and suppressed the upregulation of CGRP, c-fos and PI3K/p-Akt in the TNC. Similarly, the PI3K inhibitor LY294002 prevented nitroglycerin-induced hyperalgesia. In addition, activating GLP-1R reduced Iba-1, IL-1β and TNF-α release and inhibited TNC microglial number and morphological changes (process retraction) following nitroglycerin administration. In vitro, the protein levels of IL-1β and TNF-α in lipopolysaccharide-stimulated BV-2 microglia were also decreased by liraglutide. Conclusions: These findings suggest that microglial GLP-1R activation in the TNC may suppress the central sensitization of CM by regulating TNC microglial activation via the PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

Background: A mouse with hepatocyte‐specific deiodinase type II inactivation (Alb‐D2KO) is resistant to diet‐induced obesity, hepatic steatosis, and hypertriglyceridemia due to perinatal epigenetic modifications in the liver. This phenotype is linked to low levels of Zfp125, a hepatic transcriptional repressor that promotes liver steatosis by inhibiting genes involved in packaging and secretion of very‐low‐density lipoprotein. Methods: Here, we used chronic and binge ethanol (EtOH) in mice to cause liver steatosis. Results: The EtOH treatment causes a 2.3‐fold increase in hepatic triglyceride content; Zfp125 levels were approximately 50% higher in these animals. In contrast, Alb‐D2KO mice did not develop EtOH‐induced liver steatosis. They also failed to elevate Zfp125 to the same levels, despite being on the EtOH‐containing diet for the same period of time. Their phenotype was associated with 1.3‐ to 2.9‐fold up‐regulation of hepatic genes involved in lipid transport and export that are normally repressed by Zfp125, that is, Mttp, Abca1, Ldlr, Apoc1, Apoc3, Apoe, Apoh, and Azgp1. Furthermore, genes involved in the EtOH metabolic pathway, that is, Aldh2 and Acss2, were also 1.6‐ to 3.1‐fold up‐regulated in Alb‐D2KO EtOH mice compared with control animals kept on EtOH. Conclusions: EtOH consumption elevates expression of Zfp125. Alb‐D2KO animals, which have lower levels of Zfp125, are much less susceptible to EtOH‐induced liver steatosis. [ABSTRACT FROM AUTHOR]

Mullite is one of the popular ceramic materials for different engineering applications due to some of its important properties which include good thermal and chemical stability, high creep resistance, etc. Mullite synthesized by solgel process generally requires lower temperature for processing and generate product with better homogeneity and more purity compared with other conventional processes. Coating of solgel-derived mullite film on surface of a ceramic substrate can improve its thermomechanical properties, making it suitable for applications in different aggravated conditions. This study embarks a comprehensive review on synthesis, characterization and applications of solgel-derived mullite coating. [ABSTRACT FROM AUTHOR]

A list of plant species used for food in Hungary and among Hungarian ethnic groups of the Carpathian Basin during the 19th and 20th centuries was compiled from 71 ethnographic and ethnobotanical sources and a survey among contemporary Hungarian botanists. Species used as food, spice, beverage or occasional snacks were collected. Sources mention 236 plant species belonging to 68 families. Most wild fleshy fruits (mostly Rosa, Rubus, Cornus, Ribes, Vaccinium spp.), dry fruits and seeds (Fagus, Quercus, Corylus, Castanea, Trapa spp.), several green vegetables (e.g. Rumex, Urtica, Humulus, Chenopodiaceae spp., Ranunculusficaria), bulbs and tubers (Lathyrus tuberosus, Helianthus tuberosus, Chaerophyllum bulbosum, Allium spp.) used for food in Europe, are also known to be consumed in Hungary. A characteristic feature of Hungarian plant use was the mass consumption of the underground parts of several marsh (e.g. Typha, Phragmites, Sagittaria, Alisma, Butomus, Bolboschoenus spp., as well as the endemic Armoracia macrocarpa) and steppe species (e.g. Crambe tataria, Rumexpseudonatronatus). Consuming wild food plants is still important among Hungarians living in Transylvania: even nowadays more than 40 species are gathered and used at some locations. [ABSTRACT FROM AUTHOR]

The avoidance of being overweight or obese is a daily challenge for a growing number of people. The growing proportion of people suffering from a nutritional imbalance in many parts of the world exemplifies this challenge and emphasizes the need for a better understanding of the mechanisms that regulate nutritional balance. Until recently, research on the central regulation of food intake primarily focused on neuronal signaling, with little attention paid to the role of glial cells. Over the last few decades, our understanding of glial cells has changed dramatically. These cells are increasingly regarded as important neuronal partners, contributing not just to cerebral homeostasis, but also to cerebral signaling. Our understanding of the central regulation of energy balance is part of this (r)evolution. Evidence is accumulating that glial cells play a dynamic role in the modulation of energy balance. In the present review, we summarize recent data indicating that the multifaceted glial compartment of the brainstem dorsal vagal complex (DVC) should be considered in research aimed at identifying feeding-related processes operating at this level. [ABSTRACT FROM AUTHOR]