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| Structure and brain expression patterns of FFARs. (A) Cartoon based on FFAR1 crystal structure (PDB-ID: 4PHU) (Srivastava et al., 2014), highlighting membrane orientation and two ligand binding sites in opposite sides of the membrane. (B) Central brain section of 8-weeks, male mouse (C57BL/6J) indicating reference regions. (C-E) Brain left hemisphere sagittal projection showing expression of FFAR1, FFAR4 and GPR84, respectively, based on in situ hybridization (ISH) data. FFAR2 and FFAR3 are not shown due to its lower expression levels. (F) Quantification of relative expression from ISH data for all FFARs isoforms. AU: Arbitrary units; ICTX: Isocortex; OLF: Olfactory areas; HPF: Hyppocampal formation; CTXsp: Cortical subplate; STR: Striatum; PAL: Pallidum; TH: Thalamus; HYP: Hypothalamus; MB: Midbrain; P: Pons; MY: Medulla; and CB: Cerebellum. Image credit for panels C-E: Allen Institute © 2007 Allen Institute for Brain Science. Allen Mouse Brain Atlas. Available from: http://mouse.brain-map.org/search/. Panels B and F were constructed from data available through Allen Mouse Brain Atlas website.
Source publication
Fatty acids (FAs) are typically associated with structural and metabolic roles, as they can be stored as triglycerides, degraded by β-oxidation or used in phospholipids’ synthesis, the main components of biological membranes. It has been shown that these lipids exhibit also regulatory functions in different cell types. FAs can serve as secondary me...
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... the superfamily of GPCRs, FFARs belong to the largest subfamily of Class A/1 (rhodopsin-like) receptors, constituted by a motif of 7 transmembrane segments (TMs) and at least one longer cytosolic domain that serves as binding site for signaling machinery assembly (Dorsam and Gutkind, 2007;Heldin et al., 2016). The ligand recognition site is defined within the transmembrane helix bundle ( Figure 1A). The original cluster of FFARs was deorphanized by heterologous expression and ligand screening through monitoring cytosolic Ca +2 levels ( Briscoe et al., 2003). ...
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... the other hand, qPCR targeted experiments showed a wider expression of FFAR1 in neuronal tissues, with higher expression levels in medulla oblongata, substantia nigra and spinal cord, followed by putamen, locus cereleus, globus palidus, and amygdala ( Briscoe et al., 2003), while western blot analysis showed higher expression in pons, dentate gyrus, pituitary gland, substantia nigra and spinal cord, followed by subgranular and subventricular zones, CA1, medulla oblongata, and cerebral cortex, with minor expression in cerebellum ( Ma et al., 2007). In situ hybridization (ISH) of mice brain sagittal sections indicated discrete preferential FFAR1 expression in olfactory bulb, pons, and medulla ( Figures 1C,F), while coronal sections highlighted hippocampus and cerebral cortex ( Zamarbide et al., 2014). Its levels are weaker than in primates and, hence, it has been suggested that is not essential. ...
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... receptor is the only FFAR with solved crystal structures (PDB-ID: 5KW2, 4PHU, 5TZR and 5TZY), as different fusions to Lysozyme, and in complex with different partial and full synthetic agonists, such as TAK-875, MK-8666 or the novel compound ( Srivastava et al., 2014;Lu et al., 2017;Ho et al., 2018). Noteworthy, the different structures identified two putative binding sites in opposite sides of the transmembrane region, A1 in the extracellular side and A2 in the cytosolic one ( Figure 1A). Only the occupancy of the latter by synthetic or natural ligands promotes full agonistic response and structure of intracellular loop IC2 located between transmembrane regions TM3 and TM4, which is believed to be necessary for G-protein interaction. ...
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... low level, but widespread FFAR2 expression may be due to its presence in immune cells, such as infiltrating neutrophils and macrophages. Its expression in CNS is rather low compared to other FFARs ( Figure 1F) and limited to glia and neurons of the caudate, but FFAR2 can also be detected in cortical neurons and pituitary gland. However, the participation of FFAR2 in neuronal processes still needs further analysis. ...
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... RNAseq screening analysis of FFAR3 expression indicated a widespread, but weak pattern, with higher levels observed in adipose tissue, breast, spleen, and digestive tract. Neural expression is scarce ( Figure 1F) and only very weakly detected in the pituitary gland in GTEx (The GTEx Consortium, 2013). A GPR41-mRFP transgenic mice model published by Nohr et al. (2013) showed FFAR3 expression in the digestive tract intimately associated to the enteroendocrine system, mainly in enteric neurons of the submucosal and myenteric ganglia, and in several of the postganglionic sympathetic and sensory neurons, both in autonomic and somatic peripheral nervous system (PNS). ...
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... transmembrane regions leave N-and C-terminal segments longer than in previous FFARs, but the most notorious difference is the cytoplasmic loop between TM5 and TM6, where the GPR120S lacks 16 amino acids (from 233 Consortium, 2013). ISH of mice brain sections show FFAR4 preferential expression in medulla, pons and olfactory bulb, followed by hypothalamus and cerebellum (Figures 1D,F). ...
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... expression was confirmed by Northern-blot in brain, colon, thymus, spleen, kidney, liver, intestine, placenta, lung, leukocytes, heart, and muscle. Regarding CNS expression, it is most abundantly found in medulla and spinal cord, but also significantly in amygdala, substantia nigra, thalamus, and corpus callosum, whereas only weakly detected in other brain regions such as the cerebellum ( Wittenberger et al., 2001) (Figures 1E,F). GPR84 is activated only by medium length acyl chain FAs (C9 to C14) and does not recognize longer or shorter chain carboxylic acids, promoting Ca +2 mobilization and inhibiting cAMP production, mainly through the activation of Gα i/o ( Wang et al., 2006). ...
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The biological impacts of per- and polyfluorinated alkyl substances (PFAS) are linked to their protein interactions. Existing research has largely focused on serum albumin and liver fatty acid binding protein, and binding affinities determined with a variety of methods show high variability. Moreover, few data exist for short-chain PFAS, though the...
Citations
... [3] Fatty acid-binding proteins (FABPs) are a class of low molecular weight polygenic proteins that function as transporters by binding to hydrophobic ligands (fatty acids) with different affinities and participate in fatty acid metabolism. [4] In humans, FABPs can be classified into 10 types based on their high expression in specific tissues (Table 1) [5] FABPs as an important signaling molecule have been gradually emphasized in recent years. Multiple studies have confirmed the association of FABPs with diseases such as obesity and nonalcoholic liver disease (FABP1, FABP2, The authors have no conflicts of interest to disclose. ...
Previous studies have identified a relationship between fatty acid-binding proteins (FABPs) and immune diseases. This study aimed to investigate whether a causal relationship exists between FABPs and anaphylactic shock resulting from adverse drug reactions. Single nucleotide polymorphisms associated with FABPs were utilized as instrumental variables, sourced from the National Human Genome Research Institute-European Bioinformatics Institute Catalog of human genome-wide association studies. Data on anaphylactic shock due to adverse effects of correctly administered drugs were obtained from the FinnGen database, which includes genomic and health data from 500,000 Finnish biobank donors. A two-sample Mendelian randomization analysis was conducted to explore the causality between FABPs and anaphylactic shock due to adverse drug reactions. The analysis revealed a negative causal relationship between FABP5 (odds ratio [OR] = 0.40; 95% confidence interval [CI] = 0.17–0.92; P = .032) and FABP12 (OR = 0.77; 95% CI = 0.63–0.94; P = .009) and anaphylactic shock due to adverse drug reactions. These findings were corroborated by Mendelian randomization-Egger, weighted median, and weighted mode methods. This study provides robust evidence supporting a protective relationship between FABP5 and FABP12 and anaphylactic shock due to adverse drug reactions. Further experimental studies are warranted to elucidate the causal mechanisms and associations between FABP5, FABP12, and anaphylactic shock in the context of adverse drug reactions.
... The dynamics of how FAs are integrated into or released from phospholipids significantly influence membrane fluidity (as FAs with a high unsaturation number lead to increased membrane fluidity), which is known to be altered in disease [4]. Furthermore, FAs serve pivotal roles in cellular signaling pathways, both as direct signaling molecules [5] and as precursors to other bioactive compounds [6]. Consequently, the abundance of FA molecules within the brain affects cell signaling, membrane fluidity, and energy metabolism. ...
The dysregulation of fatty acid (FA) metabolism is linked to various brain diseases, including Alzheimer’s disease (AD). Mass spectrometry imaging (MSI) allows for the visualization of FA distribution in brain tissues but is often limited by low detection sensitivity and high background interference. In this work, we introduce a novel on-tissue chemical derivatization method for FAs using Girard’s Reagent T (GT) as a derivatization reagent combined with 2-chloro-1-methylpyridinium iodide (CMPI) as a coupling reagent and triethylamine (TEA) to provide a basic environment for the reaction. This method significantly enhances the detection sensitivity of FAs, achieving a 1000-fold improvement over traditional negative ion mode analysis. Our method enabled us to observe a notable depletion of oleic acid in the corpus callosum of AD mouse model brain tissue sections compared to wild-type control brain tissue sections. The reliability of our method was validated using LC-MS/MS, which confirmed the presence of eight distinct GT-labeled FAs across various tissue locations. This approach not only improves FA detection in brain tissues but also has the potential to provide a deeper understanding of FA dynamics associated with AD pathogenesis.
... Minichromosome maintenance proteins (MCMs) are essential subunits of the prereplication complex and may function as DNA helicases during the S phase of the cell cycle [74]. Research indicates that these genes are widely distributed across eukaryotes and archaea [75]. Specifically, MCM3 acts as a licensing factor in eukaryotic cells and is crucial for the initiation of DNA replication. ...
Ophiocordyceps sinensis is a fungus that is cultured through fermentation from wild Chinese cordyceps. While studies have examined its metabolites, the evaluation of its antioxidant capacity remains to be conducted. The antioxidant results of O. sinensis indicate that the ferric ion-reducing antioxidant power (FRAP), antioxidant capacity (2.74 ± 0.12 μmol Trolox/g), 2,2-diphenyl-1-picrylhydrazyl (DPPH•) free radical scavenging rate (60.21 ± 0.51%), and the hydroxyl free radical scavenging rate (91.83 ± 0.68%) reached a maximum on day 30. Using LC-MS/MS to measure the metabolites on D24, D30, and D36, we found that the majority of the differential accumulated metabolites (DAMs) primarily accumulate in lipids, organoheterocyclic compounds, and organic acids and their derivatives. Notably, the DAMs exhibiting high peaks include acetylcarnitine, glutathione, linoleic acid, and L-propionylcarnitine, among others. The transcriptome analysis results indicate that the differentially expressed genes (DEGs) exhibiting high expression peaks on D30 primarily included lnaA, af470, and ZEB1; high expression peaks on D24 comprised SPBC29A3.09c and YBT1; high expression peaks on D36 included dtxS1, PA1538, and katG. The combined analysis revealed significant and extremely significant positive and negative correlations between all the DAMs and DEGs. The primary enriched pathways (p < 0.05) included glutathione metabolism, tryptophan metabolism, carbon metabolism, biosynthesis of secondary metabolites, and phenylalanine metabolism. The metabolic pathway map revealed that the DAMs and DEGs influencing the antioxidant activity of O. sinensis were significantly up-regulated on D30 but down-regulated on D36. The correlation analysis suggests that an increase in the content of DEGs and DAMs promotes an increase in the levels of enzyme and non-enzyme substances, ultimately enhancing the antioxidant capacity of O. sinensis. These findings serve as a reference of how DAMs and DEGs affect the antioxidant activity of O. sinensis. This may contribute to the enhanced development and application of O. sinensis.
... Controlling the quality of indigenous vegetable oils offers a cost-effective alternative for consumers seeking healthier edible oils. Fatty acids are essential precursors for intracellular and extracellular messengers and play a vital role in cell membrane synthesis [15][16][17]. A deficiency in lipids can lead to nutritional imbalances and associated health issues. ...
... They regulate activity of dopaminergic neurons in the brain to control gut motility and other physiological behaviors [75][76][77], although interestingly they have not previously been implicated in embryogenesis and hatching. Lipids and their derivatives are required for neuronal signaling through their roles in synapse function and axonal wrapping [78,79]. Indeed, we observed increased levels of LPE and decreased ceramide phosphoethanolamine (CerPE) in dsAgTL2 embryos at 38 h post oviposition, changes that resemble Drosophila glial mutants unable to ensheathe axons [80], again suggestive of neuronal defects. ...
... In mammals, deficiencies in lipid metabolism and lipid signaling have been associated with developmental and cognitive problems as well as with neurodegenerative diseases. Imbalances in fatty acids during gestation causes altered brain development in the fetus, while severe fatty acid deprivation can impair cognitive functions (reviewed in [78]). Although we could not pinpoint the precise mechanisms behind embryonic lethality, our results show how reduced energy stored caused by impaired lipid remobilization and low TAG levels leads to the collapse of normal metabolic functions, eventually causing severe stress and cellular death. ...
Lipid metabolism is an essential component in reproductive physiology. While lipid mobilization has been implicated in the growth of Plasmodium falciparum malaria parasites in their Anopheles vectors, the role of this process in the reproductive biology of these mosquitoes remains elusive. Here, we show that impairing lipolysis in Anopheles gambiae, the major malaria vector, leads to embryonic lethality. Embryos derived from females in which we silenced the triglyceride lipase AgTL2 or the lipid storage droplet AgLSD1 develop normally during early embryogenesis but fail to hatch due to severely impaired metabolism. Embryonic lethality is efficiently recapitulated by exposing adult females to broad-spectrum lipase inhibitors prior to blood feeding, unveiling lipolysis as a potential target for inducing mosquito sterility. Our findings provide mechanistic insights into the importance of maternal lipid mobilization in embryonic health that may inform studies on human reproduction.
... Adrenic acid-derived epoxy fatty acids have anti-nociceptive properties and can reduce inflammatory pain 54 so that a link between lower levels and higher risk of DSPN appears biologically plausible. Linolenic acid and adrenic acid, or all-cis-7,10,13,16-docosatetraenoic acid, are also essential polyunsaturated fatty acids (PUFA), which are precursors of more potent derivatives such as arachidonic (omega-6, ARA) and docosahexaenoic (omega-3, DHA) acids, which serve as either building blocks of cell membrane or substrates for the synthesis of inflammation-related compounds and are involved in neural development processes 55,56 . Furthermore, DHA reduces pro-inflammatory cytokines and induces antiinflammation cytokines, which is consistent with the observed patterns of inflammatory proteins in our datasets 55 . ...
... Linolenic acid and adrenic acid, or all-cis-7,10,13,16-docosatetraenoic acid, are also essential polyunsaturated fatty acids (PUFA), which are precursors of more potent derivatives such as arachidonic (omega-6, ARA) and docosahexaenoic (omega-3, DHA) acids, which serve as either building blocks of cell membrane or substrates for the synthesis of inflammation-related compounds and are involved in neural development processes 55,56 . Furthermore, DHA reduces pro-inflammatory cytokines and induces antiinflammation cytokines, which is consistent with the observed patterns of inflammatory proteins in our datasets 55 . In addition, certain groups of GPCR called free fatty acid receptors (FFAR), such as GPR40/FFAR1 and GPR120/FFAR4, are activated by PUFAs and medium-chain fatty acids (MCFA), such as capric acid, to regulate many cellular processes, i.e. insulin secretion, inflammation, neural cognitive and sensory function 57 . ...
Background
Distal sensorimotor polyneuropathy (DSPN) is a common neurological disorder in elderly adults and people with obesity, prediabetes and diabetes and is associated with high morbidity and premature mortality. DSPN is a multifactorial disease and not fully understood yet.
Methods
Here, we developed the Interpretable Multimodal Machine Learning (IMML) framework for predicting DSPN prevalence and incidence based on sparse multimodal data. Exploiting IMMLs interpretability further empowered biomarker identification. We leveraged the population-based KORA F4/FF4 cohort including 1091 participants and their deep multimodal characterisation, i.e. clinical data, genomics, methylomics, transcriptomics, proteomics, inflammatory proteins and metabolomics.
Results
Clinical data alone is sufficient to stratify individuals with and without DSPN (AUROC = 0.752), whilst predicting DSPN incidence 6.5 ± 0.2 years later strongly benefits from clinical data complemented with two or more molecular modalities (improved ΔAUROC > 0.1, achieved AUROC of 0.714). Important and interpretable features of incident DSPN prediction include up-regulation of proinflammatory cytokines, down-regulation of SUMOylation pathway and essential fatty acids, thus yielding novel insights in the disease pathophysiology.
Conclusions
These may become biomarkers for incident DSPN, guide prevention strategies and serve as proof of concept for the utility of IMML in studying complex diseases.
... Controlling the quality of indigenous vegetable oils offers a cost-effective alternative for consumers seeking healthier edible oils. Fatty acids are essential precursors for intracellular and extracellular messengers and play a vital role in cell membrane synthesis [15][16][17]. A deficiency in lipids can lead to nutritional imbalances and associated health issues. ...
... FFAR1 participates in a wide range of physiological functions and its expression has been reported in several tissues, including the CNS. Of note, FFAR1 has been shown to be widely expressed in hypothalamic neurons directly involved in the control of energy homeostasis (64,70). In this context, a recent study has documented that central pharmacological activation of FFAR1 in diet-induced obese mice decreased body weight and increased energy expenditure, while virogenetic knockdown of FFAR1 in ARC POMC neurons of obese mice evoked hyperphagia and body weight gain, as well as the development of hepatic insulin resistance and steatosis (70). ...
... Another MCFA receptor, GPR84, has been found to be expressed also in several metabolic tissues, including the brain (71), where its presence within the hypothalamus has been reported (64). While the information of the roles of GPR84 in the central control of metabolic homeostasis remains scarce, it has been shown that icv treatment with a GPR84 agonist reduced food intake in the rainbow trout together with an increase in hypothalamic mRNA levels of POMC and CART, and a decrease in NPY and AgRP levels (71). ...
... The most prominent example is the family of peroxisome proliferator-activated receptors (PPARs), ligandactivated nuclear receptors that play a crucial role in regulating essential physiological functions, such as glucose and lipid metabolism, as well as energy balance. Upon FA binding, PPARs are translocated to the nucleus and heterodimerize with another nuclear receptor, the retinoid X receptor (RXR), acting as transcription factors by binding to peroxisome proliferator response elements (PPREs) which allows the heterodimer to activate or repress transcription (64). Three different PPAR isoforms -PPARa, PPARb/d and PPARg-have been identified, and their involvement in lipid metabolism has been well documented. ...
The hypothalamus lies at the intersection of brain and hormonal mechanisms governing essential bodily functions, including metabolic/body weight homeostasis and reproduction. While metabolism and fertility are precisely regulated by independent neuroendocrine axes, these are tightly connected, as reflection of the bidirectional interplay between the energy status of the organisms and their capacity to reproduce; a connection with important pathophysiological implications in disorders affecting these two crucial systems. Beyond the well-characterized roles of key hormones (e.g., leptin, insulin, ghrelin) and neuropeptides (e.g., melanocortins, kisspeptins) in the integral control of metabolism and reproduction, mounting evidence has pointed out a relevant function of cell energy sensors and lipid sensing mechanisms in the hypothalamic control of metabolism, with prominent roles also for metabolic sensors, such as mTOR, AMPK and SIRT1, in the nutritional regulation of key aspects of reproduction, such as pubertal maturation. We provide herein a synoptic overview of these novel regulatory pathways, with a particular focus on their putative function in the metabolic control of puberty, and delineate new avenues for further exploration of the intricate mechanisms whereby metabolism and reproduction are tightly connected.
... Our study provides evidence that the peripheral sensory process is maintained by the lipid metabolizing enzymes with putative MGAT activity, and one enzyme regulates the transcriptional level of the thermosensors IR25a and IR21a in DOCCs. Lipid metabolism is fundamental for many cellular functions ranging from cell membrane properties and lipid composition to intra-/intercellular signaling and energy storage (40,41). In particular, DAG and its metabolites play key roles in regulating the activation of sensors and other membrane molecules, thereby affecting cellular and physiological responses (26, [42][43][44]. ...
Sensory inputs of temperature dynamics in the environment are essential for appropriate physiological outputs. The responsiveness of sensory neurons is maintained by functional thermosensor expression. However, the mechanism by which their expression is regulated is unclear. In this study, we identified a monoacylglycerol acyltransferase-coding gene named bishu-1 that contributes to maintaining the responsiveness of cool temperature sensing neurons in Drosophila . bishu-1 mutation led to abnormal thermal avoidance in a cool temperature range. Cooling-induced responses in dorsal organ cool cells were weakened by the absence of bishu-1 , and this was associated with reduced transcription of the ionotropic receptors IR25a and IR21a through the transcription factor broad . Our findings unveil a novel link between lipid metabolism and thermosensor function, thus providing new insights into mechanisms underlying the appropriate maintenance of sensory inputs.
... Minichromosome maintenance proteins (MCMs) were first discovered in Saccharomyces cerevisiae. Subsequent studies have found that such genes are widely present in eukaryotes and archaea [53,54]. However, earlier studies have shown that abnormal expression and activation of the MCM complex are usually accompanied by the occurrence of various malignant tumors and accelerate unstable and uncontrolled cell cycle progression in the genome [53]. ...
During the subculture of filamentous fungi, obvious signs of degradation occur which affect the growth and development of the strain, change the content of metabolites, and interfere with gene expression. However, the specific molecular mechanism of filamentous fungi degradation is still unclear. In this study, a filamentous fungus Samsoniella hepiali was used as the research object, and it was continuously subcultured. The results showed that when the strain was subcultured to the F8 generation, the strain began to show signs of degradation, which was manifested by affecting the apparent morphology, reducing the growth rate and sporulation, and destroying the antioxidant system. Further transcriptome and metabolomics analyses were performed, and the results showed differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) that were mainly enriched in four metabolic pathways: ABC transporters; fatty acid degradation; alanine, aspartate, and glutamate metabolism; and purine metabolism. Many of the metabolites that were significantly enriched in different pathways may mainly be regulated by genes belonging to proteins and enzymes, such as Abcd3, Ass1, and Pgm1. At the same time, in the process of subculture, many genes and metabolites that can induce apoptosis and senescence continue to accumulate, causing cell damage and consuming a lot of energy, which ultimately leads to the inhibition of mycelial growth. In summary, this study clarified the response of S. hepiali strains to key metabolic pathways during subculture and some reasons for the degradation of strains.
